Structure-activity relationships of cannabinoids: A joint CoMFA and pseudoreceptor modelling study

NASA Astrophysics Data System (ADS)

Schmetzer, Silke; Greenidge, Paulette; Kovar, Karl-Artur; Schulze-Alexandru, Meike; Folkers, Gerd

1997-05-01

A cannabinoid pseudoreceptor model for the CB1-receptor has been constructed for 31 cannabinoids using the molecular modelling software YAK. Additionally, two CoMFA studies were performed on these ligands, the first of which was conducted prior to the building of the pseudoreceptor. Its pharmacophore is identical with the initial superposition of ligands used for pseudoreceptor construction. In contrast, the ligand alignment for the second CoMFA study was taken directly from the final cannabinoid pseudoreceptor model. This altered alignment gives markedly improved cross-validated r2 values as compared to those obtained from the original alignment with{{r}}_{{{cross}}}^2 values of 0.79 and 0.63, respectively, for five components. However, the pharmacophore alignment has the better predictive ability. Both the CoMFA and pseudoreceptor methods predict the free energy of binding of test ligands well.

Toward the identification of a reliable 3D-QSAR model for the protein tyrosine phosphatase 1B inhibitors

NASA Astrophysics Data System (ADS)

Wang, Fangfang; Zhou, Bo

2018-04-01

Protein tyrosine phosphatase 1B (PTP1B) is an intracellular non-receptor phosphatase that is implicated in signal transduction of insulin and leptin pathways, thus PTP1B is considered as potential target for treating type II diabetes and obesity. The present article is an attempt to formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling of a series of compounds possessing PTP1B inhibitory activities using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The optimum template ligand-based models are statistically significant with great CoMFA (R2cv = 0.600, R2pred = 0.6760) and CoMSIA (R2cv = 0.624, R2pred = 0.8068) values. Molecular docking was employed to elucidate the inhibitory mechanisms of this series of compounds against PTP1B. In addition, the CoMFA and CoMSIA field contour maps agree well with the structural characteristics of the binding pocket of PTP1B active site. The knowledge of structure-activity relationship and ligand-receptor interactions from 3D-QSAR model and molecular docking will be useful for better understanding the mechanism of ligand-receptor interaction and facilitating development of novel compounds as potent PTP1B inhibitors.

3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model.

PubMed

Ul-Haq, Zaheer; Ashraf, Sajda; Al-Majid, Abdullah Mohammed; Barakat, Assem

2016-04-30

Urease enzyme (EC 3.5.1.5) has been determined as a virulence factor in pathogenic microorganisms that are accountable for the development of different diseases in humans and animals. In continuance of our earlier study on the helicobacter pylori urease inhibition by barbituric acid derivatives, 3D-QSAR (three dimensional quantitative structural activity relationship) advance studies were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods. Different partial charges were calculated to examine their consequences on the predictive ability of the developed models. The finest developed model for CoMFA and CoMSIA were achieved by using MMFF94 charges. The developed CoMFA model gives significant results with cross-validation (q²) value of 0.597 and correlation coefficients (r²) of 0.897. Moreover, five different fields i.e., steric, electrostatic, and hydrophobic, H-bond acceptor and H-bond donors were used to produce a CoMSIA model, with q² and r² of 0.602 and 0.98, respectively. The generated models were further validated by using an external test set. Both models display good predictive power with r²pred ≥ 0.8. The analysis of obtained CoMFA and CoMSIA contour maps provided detailed insight for the promising modification of the barbituric acid derivatives with an enhanced biological activity.

LFER and CoMFA studies on optical resolution of alpha-alkyl alpha-aryloxy acetic acid methyl esters on DACH-DNB chiral stationary phase.

PubMed

Carotti, A; Altomare, C; Cellamare, S; Monforte, A; Bettoni, G; Loiodice, F; Tangari, N; Tortorella, V

1995-04-01

The HPLC resolution of a series of racemic alpha-substituted alpha-aryloxy acetic acid methyl esters I on a pi-acid N,N'-(3,5-dinitrobenzoyl)-trans-1,2-diaminocyclohexane as chiral selector was modelled by linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). Our results indicate that the retention process mainly depends on solute lipophilicity and steric properties, whereas enantioselectivity is primarily influenced by electrostatic and steric interactions. CoMFA provided additional information with respect to the LFER study, allowed the mixing of different subsets of I and led to a quantitative 3D model of steric and electrostatic factors responsible for chiral recognition.

3D-QSAR and docking studies of flavonoids as potent Escherichia coli inhibitors

PubMed Central

Fang, Yajing; Lu, Yulin; Zang, Xixi; Wu, Ting; Qi, XiaoJuan; Pan, Siyi; Xu, Xiaoyun

2016-01-01

Flavonoids are potential antibacterial agents. However, key substituents and mechanism for their antibacterial activity have not been fully investigated. The quantitative structure-activity relationship (QSAR) and molecular docking of flavonoids relating to potent anti-Escherichia coli agents were investigated. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were developed by using the pIC50 values of flavonoids. The cross-validated coefficient (q2) values for CoMFA (0.743) and for CoMSIA (0.708) were achieved, illustrating high predictive capabilities. Selected descriptors for the CoMFA model were ClogP (logarithm of the octanol/water partition coefficient), steric and electrostatic fields, while, ClogP, electrostatic and hydrogen bond donor fields were used for the CoMSIA model. Molecular docking results confirmed that half of the tested flavonoids inhibited DNA gyrase B (GyrB) by interacting with adenosine-triphosphate (ATP) pocket in a same orientation. Polymethoxyl flavones, flavonoid glycosides, isoflavonoids changed their orientation, resulting in a decrease of inhibitory activity. Moreover, docking results showed that 3-hydroxyl, 5-hydroxyl, 7-hydroxyl and 4-carbonyl groups were found to be crucial active substituents of flavonoids by interacting with key residues of GyrB, which were in agreement with the QSAR study results. These results provide valuable information for structure requirements of flavonoids as antibacterial agents. PMID:27049530

Investigation of antigen-antibody interactions of sulfonamides with a monoclonal antibody in a fluorescence polarization immunoassay using 3D-QSAR models

USDA-ARS?s Scientific Manuscript database

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular si...

3D-QSAR studies on the inhibitory activity of trimethoprim analogues against Escherichia coli dihydrofolate reductase.

PubMed

Vijayaraj, Ramadoss; Devi, Mekapothula Lakshmi Vasavi; Subramanian, Venkatesan; Chattaraj, Pratim Kumar

2012-06-01

Three-dimensional quantitative structure activity relationship (3D-QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4-diamino-5-(substituted-benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. To construct highly predictive 3D-QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models show statistically significant cross-validated and non-cross-validated correlation coefficient of r2 CV and r2 nCV, respectively. The final 3D-QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the substitution of electronegative groups at the first and second position along with electropositive group at the third position of R2 substitution significantly increases the potency of the derivatives. The results obtained from the CoMFA and CoMSIA study delineate the substituents on the trimethoprim analogues responsible for the enhanced potency and also provide valuable directions for the design of new trimethoprim analogues with improved affinity. © 2012 John Wiley & Sons A/S.

Three-dimensional quantitative structure-activity relationship CoMSIA/CoMFA and LeapFrog studies on novel series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists.

PubMed

Morales-Bayuelo, Alejandro; Ayazo, Hernan; Vivas-Reyes, Ricardo

2010-10-01

Comparative molecular similarity indices analysis (CoMSIA) and comparative molecular field analysis (CoMFA) were performed on a series of bicyclo [4.1.0] heptanes derivatives as melanin-concentrating hormone receptor R1 antagonists (MCHR1 antagonists). Molecular superimposition of antagonists on the template structure was performed by database alignment method. The statistically significant model was established on sixty five molecules, which were validated by a test set of ten molecules. The CoMSIA model yielded the best predictive model with a q(2) = 0.639, non cross-validated R(2) of 0.953, F value of 92.802, bootstrapped R(2) of 0.971, standard error of prediction = 0.402, and standard error of estimate = 0.146 while the CoMFA model yielded a q(2) = 0.680, non cross-validated R(2) of 0.922, F value of 114.351, bootstrapped R(2) of 0.925, standard error of prediction = 0.364, and standard error of estimate = 0.180. CoMFA analysis maps were employed for generating a pseudo cavity for LeapFrog calculation. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. The results show the variability of steric and electrostatic contributions that determine the activity of the MCHR1 antagonist, with these results we proposed new antagonists that may be more potent than previously reported, these novel antagonists were designed from the addition of highly electronegative groups in the substituent di(i-C(3)H(7))N- of the bicycle [4.1.0] heptanes, using the model CoMFA which also was used for the molecular design using the technique LeapFrog. The data generated from the present study will further help to design novel, potent, and selective MCHR1 antagonists. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Molecular docking and 3D-QSAR studies on triazolinone and pyridazinone, non-nucleoside inhibitor of HIV-1 reverse transcriptase.

PubMed

Sivan, Sree Kanth; Manga, Vijjulatha

2010-06-01

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric inhibitors of the HIV-1 reverse transcriptase. Recently a series of Triazolinone and Pyridazinone were reported as potent inhibitors of HIV-1 wild type reverse transcriptase. In the present study, docking and 3D quantitative structure activity relationship (3D QSAR) studies involving comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 31 molecules. Ligands were built and minimized using Tripos force field and applying Gasteiger-Hückel charges. These ligands were docked into protein active site using GLIDE 4.0. The docked poses were analyzed; the best docked poses were selected and aligned. CoMFA and CoMSIA fields were calculated using SYBYL6.9. The molecules were divided into training set and test set, a PLS analysis was performed and QSAR models were generated. The model showed good statistical reliability which is evident from the r2 nv, q2 loo and r2 pred values. The CoMFA model provides the most significant correlation of steric and electrostatic fields with biological activities. The CoMSIA model provides a correlation of steric, electrostatic, acceptor and hydrophobic fields with biological activities. The information rendered by 3D QSAR model initiated us to optimize the lead and design new potential inhibitors.

Design of Novel Chemotherapeutic Agents Targeting Checkpoint Kinase 1 Using 3D-QSAR Modeling and Molecular Docking Methods.

PubMed

Balupuri, Anand; Balasubramanian, Pavithra K; Cho, Seung J

2016-01-01

Checkpoint kinase 1 (Chk1) has emerged as a potential therapeutic target for design and development of novel anticancer drugs. Herein, we have performed three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking analyses on a series of diazacarbazoles to design potent Chk1 inhibitors. 3D-QSAR models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. Docking studies were performed using AutoDock. The best CoMFA and CoMSIA models exhibited cross-validated correlation coefficient (q2) values of 0.631 and 0.585, and non-cross-validated correlation coefficient (r2) values of 0.933 and 0.900, respectively. CoMFA and CoMSIA models showed reasonable external predictabilities (r2 pred) of 0.672 and 0.513, respectively. A satisfactory performance in the various internal and external validation techniques indicated the reliability and robustness of the best model. Docking studies were performed to explore the binding mode of inhibitors inside the active site of Chk1. Molecular docking revealed that hydrogen bond interactions with Lys38, Glu85 and Cys87 are essential for Chk1 inhibitory activity. The binding interaction patterns observed during docking studies were complementary to 3D-QSAR results. Information obtained from the contour map analysis was utilized to design novel potent Chk1 inhibitors. Their activities and binding affinities were predicted using the derived model and docking studies. Designed inhibitors were proposed as potential candidates for experimental synthesis.

Antitumor evaluation and 3D-QSAR studies of a new series of the spiropyrroloquinoline isoindolinone/aza-isoindolinone derivatives by comparative molecular field analysis (CoMFA).

PubMed

Sadeghzadeh, Masoud; Salahinejad, Maryam; Zarezadeh, Nahid; Ghandi, Mehdi; Baghery, Maryam Keshavarz

2017-11-01

In current study, antitumor activity of two series of the newly synthesized spiropyrroloquinoline isoindolinone and spiropyrroloquinoline aza-isoindolinone scaffolds was evaluated against three human breast normal and cancer cell lines (MCF-10A, MCF-7 and SK-BR-3) and compared with cytotoxicity values of doxorubicin and colchicine as the standard drugs. It was found that several compounds were endowed with cytotoxicity in the low micromolar range. Among these two series, compounds 6i, 6j, 6k and 7l, 7m, 7n, 7o containing 3-ethyl-1H-indole moiety were found to be highly effective against both cancer cell lines ranging from [Formula: see text] to [Formula: see text] in comparison with the corresponding analogs. Compared with human cancer cells, the most potent compounds did not show high cytotoxicity against human breast normal MCF-10A cells. Generally, most of the evaluated compounds 6a-l and 7a-o series showed more antitumor activity against SK-BR-3 than MCF-7 cells. Moreover, comparative molecular field analysis (CoMFA) as a popular tools of three-dimensional quantitative structure-activity relationship (3D-QSAR) studies was carried out on 27 spiropyrroloquinolineisoindolinone and spiropyrroloquinolineaza-isoindolinone derivatives with antitumor activity against on SK-BR-3 cells. The obtained CoMFA models showed statistically excellent performance, which also possessed good predictive ability for an external test set. The results confirm the important effect of molecular steric and electrostatic interactions of these compounds on in vitro cytotoxicity against SK-BR-3.

Rational design of methicillin resistance staphylococcus aureus inhibitors through 3D-QSAR, molecular docking and molecular dynamics simulations.

PubMed

Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

2018-04-01

Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q 2 of 0.578, R 2 of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q 2 of 0.554, R 2 of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r 2 Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular docking and 3D-QSAR studies on inhibitors of DNA damage signaling enzyme human PARP-1.

PubMed

Fatima, Sabiha; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

2012-08-01

Poly (ADP-ribose) polymerase-1 (PARP-1) operates in a DNA damage signaling network. Molecular docking and three dimensional-quantitative structure activity relationship (3D-QSAR) studies were performed on human PARP-1 inhibitors. Docked conformation obtained for each molecule was used as such for 3D-QSAR analysis. Molecules were divided into a training set and a test set randomly in four different ways, partial least square analysis was performed to obtain QSAR models using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Derived models showed good statistical reliability that is evident from their r², q²(loo) and r²(pred) values. To obtain a consensus for predictive ability from all the models, average regression coefficient r²(avg) was calculated. CoMFA and CoMSIA models showed a value of 0.930 and 0.936, respectively. Information obtained from the best 3D-QSAR model was applied for optimization of lead molecule and design of novel potential inhibitors.

3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors.

PubMed

Chitta, Aparna; Sivan, Sree Kanth; Manga, Vijjulatha

2014-06-01

To understand the structural requirements of 5-hydroxytryptamine (5HT7) receptor inhibitors and to design new ligands against 5HT7 receptor with enhanced inhibitory potency, a three-dimensional quantitative structure-activity relationship study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a data set of 56 molecules consisting of oxindole, tetrahydronaphthalene, aryl ketone substituted arylpiperazinealkylamide derivatives was performed. Derived model showed good statistical reliability in terms of predicting 5HT7 inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like conventional r2 and a cross validated (q2) values of 0.985, 0.743 for CoMFA and 0.970, 0.608 for CoMSIA, respectively. Predictive ability of the models to determine 5HT7 antagonistic activity is validated using a test set of 16 molecules that were not included in the training set. Predictive r2 obtained for the test set was 0.560 and 0.619 for CoMFA and CoMSIA, respectively. Steric, electrostatic fields majorly contributed toward activity which forms the basis for design of new molecules. Absorption, distribution, metabolism and elimination (ADME) calculation using QikProp 2.5 (Schrodinger 2010, Portland, OR) reveals that the molecules confer to Lipinski's rule of five in majority of the cases.

A systematic quantitative approach to rational drug design and discovery of novel human carbonic anhydrase IX inhibitors.

PubMed

Sethi, Kalyan K; Verma, Saurabh M

2014-08-01

Drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed for a series of carbonic anhydrase IX inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques with the help of SYBYL 7.1 software. The large set of 36 different aromatic/heterocyclic sulfamates carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, such as hCA IX, was chosen for this study. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) values 0.802 and 0.829 and r(2) values 1.000 and 0.994 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. The predicted r(2) values are 0.999 and 0.502 for CoMFA and CoMSIA, respectively. SEA (steric, electrostatic, hydrogen bond acceptor) of CoMSIA has the significant contribution for the model development. The docking of inhibitors into hCA IX active site using Glide XP (Schrödinger) software revealed the vital interactions and binding conformation of the inhibitors. The CoMFA and CoMSIA field contour maps are well in agreement with the structural characteristics of the binding pocket of hCA IX active site, which suggests that the information rendered by 3D-QSAR models and the docking interactions can provide guidelines for the development of improved hCA IX inhibitors as leads for various types of metastatic cancers including those of cervical, renal, breast and head and neck origin.

CoMFA analyses of C-2 position salvinorin A analogs at the kappa-opioid receptor provides insights into epimer selectivity.

PubMed

McGovern, Donna L; Mosier, Philip D; Roth, Bryan L; Westkaemper, Richard B

2010-04-01

The highly potent and kappa-opioid (KOP) receptor-selective hallucinogen Salvinorin A and selected analogs have been analyzed using the 3D quantitative structure-affinity relationship technique Comparative Molecular Field Analysis (CoMFA) in an effort to derive a statistically significant and predictive model of salvinorin affinity at the KOP receptor and to provide additional statistical support for the validity of previously proposed structure-based interaction models. Two CoMFA models of Salvinorin A analogs substituted at the C-2 position are presented. Separate models were developed based on the radioligand used in the kappa-opioid binding assay, [(3)H]diprenorphine or [(125)I]6 beta-iodo-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([(125)I]IOXY). For each dataset, three methods of alignment were employed: a receptor-docked alignment derived from the structure-based docking algorithm GOLD, another from the ligand-based alignment algorithm FlexS, and a rigid realignment of the poses from the receptor-docked alignment. The receptor-docked alignment produced statistically superior results compared to either the FlexS alignment or the realignment in both datasets. The [(125)I]IOXY set (Model 1) and [(3)H]diprenorphine set (Model 2) gave q(2) values of 0.592 and 0.620, respectively, using the receptor-docked alignment, and both models produced similar CoMFA contour maps that reflected the stereoelectronic features of the receptor model from which they were derived. Each model gave significantly predictive CoMFA statistics (Model 1 PSET r(2)=0.833; Model 2 PSET r(2)=0.813). Based on the CoMFA contour maps, a binding mode was proposed for amine-containing Salvinorin A analogs that provides a rationale for the observation that the beta-epimers (R-configuration) of protonated amines at the C-2 position have a higher affinity than the corresponding alpha-epimers (S-configuration). (c) 2010. Published by Elsevier Inc.

Investigation of Antigen-Antibody Interactions of Sulfonamides with a Monoclonal Antibody in a Fluorescence Polarization Immunoassay Using 3D-QSAR Models

PubMed Central

Wang, Zhanhui; Kai, Zhenpeng; Beier, Ross C.; Shen, Jianzhong; Yang, Xinling

2012-01-01

A three-dimensional quantitative structure-activity relationship (3D-QSAR) model of sulfonamide analogs binding a monoclonal antibody (MAbSMR) produced against sulfamerazine was carried out by Distance Comparison (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The affinities of the MAbSMR, expressed as Log10IC50, for 17 sulfonamide analogs were determined by competitive fluorescence polarization immunoassay (FPIA). The results demonstrated that the proposed pharmacophore model containing two hydrogen-bond acceptors, two hydrogen-bond donors and two hydrophobic centers characterized the structural features of the sulfonamides necessary for MAbSMR binding. Removal of two outliers from the initial set of 17 sulfonamide analogs improved the predictability of the models. The 3D-QSAR models of 15 sulfonamides based on CoMFA and CoMSIA resulted in q2 cv values of 0.600 and 0.523, and r2 values of 0.995 and 0.994, respectively, which indicates that both methods have significant predictive capability. Connolly surface analysis, which mainly focused on steric force fields, was performed to complement the results from CoMFA and CoMSIA. This novel study combining FPIA with pharmacophore modeling demonstrates that multidisciplinary research is useful for investigating antigen-antibody interactions and also may provide information required for the design of new haptens. PMID:22754368

Three-dimensional quantitative structure-activity relationship studies on UGT1A9-mediated 3-O-glucuronidation of natural flavonols using a pharmacophore-based comparative molecular field analysis model.

PubMed

Wu, Baojian; Morrow, John Kenneth; Singh, Rashim; Zhang, Shuxing; Hu, Ming

2011-02-01

Glucuronidation is often recognized as one of the rate-determining factors that limit the bioavailability of flavonols. Hence, design and synthesis of more bioavailable flavonols would benefit from the establishment of predictive models of glucuronidation using kinetic parameters [e.g., K(m), V(max), intrinsic clearance (CL(int)) = V(max)/K(m)] derived for flavonols. This article aims to construct position (3-OH)-specific comparative molecular field analysis (CoMFA) models to describe UDP-glucuronosyltransferase (UGT) 1A9-mediated glucuronidation of flavonols, which can be used to design poor UGT1A9 substrates. The kinetics of recombinant UGT1A9-mediated 3-O-glucuronidation of 30 flavonols was characterized, and kinetic parameters (K(m), V(max), CL(int)) were obtained. The observed K(m), V(max), and CL(int) values of 3-O-glucuronidation ranged from 0.04 to 0.68 μM, 0.04 to 12.95 nmol/mg/min, and 0.06 to 109.60 ml/mg/min, respectively. To model UGT1A9-mediated glucuronidation, 30 flavonols were split into the training (23 compounds) and test (7 compounds) sets. These flavonols were then aligned by mapping the flavonols to specific common feature pharmacophores, which were used to construct CoMFA models of V(max) and CL(int), respectively. The derived CoMFA models possessed good internal and external consistency and showed statistical significance and substantive predictive abilities (V(max) model: q(2) = 0.738, r(2) = 0.976, r(pred)(2) = 0.735; CL(int) model: q(2) = 0.561, r(2) = 0.938, r(pred)(2) = 0.630). The contour maps derived from CoMFA modeling clearly indicate structural characteristics associated with rapid or slow 3-O-glucuronidation. In conclusion, the approach of coupling CoMFA analysis with a pharmacophore-based structural alignment is viable for constructing a predictive model for regiospecific glucuronidation rates of flavonols by UGT1A9.

Design and prediction of new acetylcholinesterase inhibitor via quantitative structure activity relationship of huprines derivatives.

PubMed

Zhang, Shuqun; Hou, Bo; Yang, Huaiyu; Zuo, Zhili

2016-05-01

Acetylcholinesterase (AChE) is an important enzyme in the pathogenesis of Alzheimer's disease (AD). Comparative quantitative structure-activity relationship (QSAR) analyses on some huprines inhibitors against AChE were carried out using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and hologram QSAR (HQSAR) methods. Three highly predictive QSAR models were constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have values of r (2) = 0.988, q (2) = 0.757, ONC = 6; r (2) = 0.966, q (2) = 0.645, ONC = 5; and r (2) = 0.957, q (2) = 0.736, ONC = 6. The predictabilities were validated using an external test sets, and the predictive r (2) values obtained by the three models were 0.984, 0.973, and 0.783, respectively. The analysis was performed by combining the CoMFA and CoMSIA field distributions with the active sites of the AChE to further understand the vital interactions between huprines and the protease. On the basis of the QSAR study, 14 new potent molecules have been designed and six of them are predicted to be more active than the best active compound 24 described in the literature. The final QSAR models could be helpful in design and development of novel active AChE inhibitors.

A pharmacophore model specific to active site of CYP1A2 with a novel molecular modeling explorer and CoMFA.

PubMed

Zhang, Tao; Wei, Dong-Qing; Chou, Kuo-Chen

2012-03-01

Comparative molecular field analysis (CoMFA) is a widely used 3D-QSAR method by which we can investigate the potential relation between biological activity of compounds and their structural features. In this study, a new application of this approach is presented by combining the molecular modeling with a new developed pharmacophore model specific to CYP1A2 active site. During constructing the model, we used the molecular dynamics simulation and molecular docking method to select the sensible binding conformations for 17 CYP1A2 substrates based on the experimental data. Subsequently, the results obtained via the alignment of binding conformations of substrates were projected onto the active- site residues, upon which a simple blueprint of active site was produced. It was validated by the experimental and computational results that the model did exhibit the high degree of rationality and provide useful insights into the substrate binding. It is anticipated that our approach can be extended to investigate the protein-ligand interactions for many other enzyme-catalyzed systems as well.

Three-dimensional quantitative structure-activity relationship studies on novel series of benzotriazine based compounds acting as Src inhibitors using CoMFA and CoMSIA.

PubMed

Gueto, Carlos; Ruiz, José L; Torres, Juan E; Méndez, Jefferson; Vivas-Reyes, Ricardo

2008-03-01

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of benzotriazine derivatives, as Src inhibitors. Ligand molecular superimposition on the template structure was performed by database alignment method. The statistically significant model was established of 72 molecules, which were validated by a test set of six compounds. The CoMFA model yielded a q(2)=0.526, non cross-validated R(2) of 0.781, F value of 88.132, bootstrapped R(2) of 0.831, standard error of prediction=0.587, and standard error of estimate=0.351 while the CoMSIA model yielded the best predictive model with a q(2)=0.647, non cross-validated R(2) of 0.895, F value of 115.906, bootstrapped R(2) of 0.953, standard error of prediction=0.519, and standard error of estimate=0.178. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that small steric volumes in the hydrophobic region, electron-withdrawing groups next to the aryl linker region, and atoms close to the solvent accessible region increase the Src inhibitory activity of the compounds. In fact, adding substituents at positions 5, 6, and 8 of the benzotriazine nucleus were generated new compounds having a higher predicted activity. The data generated from the present study will further help to design novel, potent, and selective Src inhibitors as anticancer therapeutic agents.

Quantitative insights for the design of substrate-based SIRT1 inhibitors.

PubMed

Kokkonen, Piia; Mellini, Paolo; Nyrhilä, Olli; Rahnasto-Rilla, Minna; Suuronen, Tiina; Kiviranta, Päivi; Huhtiniemi, Tero; Poso, Antti; Jarho, Elina; Lahtela-Kakkonen, Maija

2014-08-01

Sirtuin 1 (SIRT1) is the most studied human sirtuin and it catalyzes the deacetylation reaction of acetylated lysine residues of its target proteins, for example histones. It is a promising drug target in the treatment of age-related diseases, such as neurodegenerative diseases and cancer. In this study, a series of known substrate-based sirtuin inhibitors was analyzed with comparative molecular field analysis (CoMFA), which is a three-dimensional quantitative structure-activity relationships (3D-QSAR) technique. The CoMFA model was validated both internally and externally, producing the statistical values concordance correlation coefficient (CCC) of 0.88, the mean value r(2)m of 0.66 and Q(2)F3 of 0.89. Based on the CoMFA interaction contours, 13 new potential inhibitors with high predicted activity were designed, and the activities were verified by in vitro measurements. This work proposes an effective approach for the design and activity prediction of new potential substrate-based SIRT1 inhibitors. Copyright © 2014 Elsevier B.V. All rights reserved.

Substituent effects on the enantioselective retention of anti-HIV 5-aryl-delta 2-1,2,4-oxadiazolines on R,R-DACH-DNB chiral stationary phase.

PubMed

Altomare, C; Cellamare, S; Carotti, A; Barreca, M L; Chimirri, A; Monforte, A M; Gasparrini, F; Villani, C; Cirilli, M; Mazza, F

1996-01-01

A series of racemic 3-phenyl-4-(1-adamantyl)-5-X-phenyl- delta 2-1,2,4-oxadiazo lines (PAdOx) were directly resolved by HPLC using a Pirkle-type stationary phase containing N,N'-(3,5-dinitrobenzoyl)-1(R),2(R)-diaminocyclohexane as chiral selector. The more retained enantiomers have S configuration, as demonstrated by X-ray crystallography and circular dichroism measurements. The influence of aromatic ring substituents on enantioselective retention was quantitatively assessed by traditional linear free energy-related (LFER) equations and comparative molecular field analysis (CoMFA). In good agreement with previous findings, the results from this study indicate that the increase in retention (k') is favoured mainly by the phi-basicity and the hydrophilicity of solute, whereas enantioselectivity (alpha) can be satisfactorily modeled by electronic and bulk parameters or CoMFA descriptors. The LFER equations and CoMFA models gave helpful insights into chiral recognition mechanisms.

QSAR and molecular modelling studies on B-DNA recognition of minor groove binders.

PubMed

de Oliveira, André Mauricio; Custódio, Flávia Beatriz; Donnici, Cláudio Luis; Montanari, Carlos Alberto

2003-02-01

Aromatic bisamidines have been proved to be efficient compounds against Leishmania spp. and Pneumocystis carinii. Although the mode of action is still not known, these molecules are supposed to be DNA minor groove binders (MGBs). This paper describes a molecular modelling study for a set of MGBs in order to rank them through their complementarity to the Dickerson Drew Dodecamer (DDD) according to their interaction energies with B-DNA. A comparative molecular field analysis (CoMFA) has shown the importance of relatively bulky positively charged groups attached to the MGB aromatic rings, and small and negatively charged substituents into the middle chain. Models were obtained for DNA denaturation related to H-bonding processes of binding modes. Validation of the model demonstrated the robustness of CoMFA in terms of independent test set of similar MGBs. GRID results allotted bioisosteric substitution of z.sbnd;Oz.sbnd; by z.sbnd;NHz.sbnd; in furan ring of furamidine and related compounds as being capable to enhance the binding to DDD.

Design new P-glycoprotein modulators based on molecular docking and CoMFA study of α, β-unsaturated carbonyl-based compounds and oxime analogs as anticancer agents

NASA Astrophysics Data System (ADS)

Sepehri, Bakhtyar; Ghavami, Raouf

2017-02-01

In this research, molecular docking and CoMFA were used to determine interactions of α, β-unsaturated carbonyl-based compounds and oxime analogs with P-glycoprotein and prediction of their activity. Molecular docking study shown these molecules establish strong Van der Waals interactions with side chain of PHE-332, PHE-728 and PHE-974. Based on the effect of component numbers on squared correlation coefficient for cross validation tests (including leave-one-out and leave-many-out), CoMFA models with five components were built to predict pIC50 of molecules in seven cancer cell lines (including Panc-1 (pancreas cancer cell line), PaCa-2 (pancreatic carcinoma cell line), MCF-7 (breast cancer cell line), A-549 (epithelial), HT-29 (colon cancer cell line), H-460 (lung cancer cell line), PC-3 (prostate cancer cell line)). R2 values for training and test sets were in the range of 0.94-0.97 and 0.84 to 0.92, respectively, and for LOO and LMO cross validation test, q2 values were in the range of 0.75-0.82 and 0.65 to 0.73, respectively. Based on molecular docking results and extracted steric and electrostatic contour maps for CoMFA models, four new molecules with higher activity with respect to the most active compound in data set were designed.

Combined 3D-QSAR and molecular docking study on 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazoline series compounds to understand the binding mechanism of DHFR inhibitors

NASA Astrophysics Data System (ADS)

Aouidate, Adnane; Ghaleb, Adib; Ghamali, Mounir; Chtita, Samir; Choukrad, M'barek; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

2017-07-01

A series of nineteen DHFR inhibitors was studied based on the combination of two computational techniques namely, three-dimensional quantitative structure activity relationship (3D-QSAR) and molecular docking. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) were developed using 19 molecules having pIC50 ranging from 9.244 to 5.839. The best CoMFA and CoMSIA models show conventional determination coefficients R2 of 0.96 and 0.93 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.64 and 0.72, respectively. The predictive ability of those models was evaluated by the external validation using a test set of five compounds with predicted determination coefficients R2test of 0.92 and 0.94, respectively. The binding mode between this kind of compounds and the DHFR enzyme in addition to the key amino acid residues were explored by molecular docking simulation. Contour maps and molecular docking identified that the R1 and R2 natures at the pyrazole moiety are the important features for the optimization of the binding affinity to the DHFR receptor. According to the good concordance between the CoMFA/CoMSIA contour maps and docking results, the obtained information was explored to design novel molecules.

Three-dimensional quantitative structure-activity relationship analysis for human pregnane X receptor for the prediction of CYP3A4 induction in human hepatocytes: structure-based comparative molecular field analysis.

PubMed

Handa, Koichi; Nakagome, Izumi; Yamaotsu, Noriyuki; Gouda, Hiroaki; Hirono, Shuichi

2015-01-01

The pregnane X receptor [PXR (NR1I2)] induces the expression of xenobiotic metabolic genes and transporter genes. In this study, we aimed to establish a computational method for quantifying the enzyme-inducing potencies of different compounds via their ability to activate PXR, for the application in drug discovery and development. To achieve this purpose, we developed a three-dimensional quantitative structure-activity relationship (3D-QSAR) model using comparative molecular field analysis (CoMFA) for predicting enzyme-inducing potencies, based on computer-ligand docking to multiple PXR protein structures sampled from the trajectory of a molecular dynamics simulation. Molecular mechanics-generalized born/surface area scores representing the ligand-protein-binding free energies were calculated for each ligand. As a result, the predicted enzyme-inducing potencies for compounds generated by the CoMFA model were in good agreement with the experimental values. Finally, we concluded that this 3D-QSAR model has the potential to predict the enzyme-inducing potencies of novel compounds with high precision and therefore has valuable applications in the early stages of the drug discovery process. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Comparative molecular field analysis of artemisinin derivatives: Ab initio versus semiempirical optimized structures

NASA Astrophysics Data System (ADS)

Tonmunphean, Somsak; Kokpol, Sirirat; Parasuk, Vudhichai; Wolschann, Peter; Winger, Rudolf H.; Liedl, Klaus R.; Rode, Bernd M.

1998-07-01

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.

Hologram quantitative structure-activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors.

PubMed

Magalhães, Uiaran de Oliveira; Souza, Alessandra Mendonça Teles de; Albuquerque, Magaly Girão; Brito, Monique Araújo de; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

2013-01-01

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure-activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q (2) = 0.802, r (2) = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2-5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q (2) = 0.748, r (2) = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives.

Hologram quantitative structure–activity relationship and comparative molecular field analysis studies within a series of tricyclic phthalimide HIV-1 integrase inhibitors

PubMed Central

de Oliveira Magalhães, Uiaran; de Souza, Alessandra Mendonça Teles; Albuquerque, Magaly Girão; de Brito, Monique Araújo; Bello, Murilo Lamim; Cabral, Lucio Mendes; Rodrigues, Carlos Rangel

2013-01-01

Acquired immunodeficiency syndrome is a public health problem worldwide caused by the Human immunodeficiency virus (HIV). Treatment with antiretroviral drugs is the best option for viral suppression, reducing morbidity and mortality. However, viral resistance in HIV-1 therapy has been reported. HIV-1 integrase (IN) is an essential enzyme for effective viral replication and an attractive target for the development of new inhibitors. In the study reported here, two- and three-dimensional quantitative structure–activity relationship (2D/3D-QSAR) studies, applying hologram quantitative structure–activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, respectively, were performed on a series of tricyclic phthalimide HIV-1 IN inhibitors. The best HQSAR model (q2 = 0.802, r2 = 0.972) was obtained using atoms, bonds, and connectivity as the fragment distinction, a fragment size of 2–5 atoms, hologram length of 61 bins, and six components. The best CoMFA model (q2 = 0.748, r2 = 0.974) was obtained with alignment of all atoms of the tricyclic phthalimide moiety (alignment II). The HQSAR contribution map identified that the carbonyl-hydroxy-aromatic nitrogen motif made a positive contribution to the activity of the compounds. Furthermore, CoMFA contour maps suggested that bulky groups in meta and para positions in the phenyl ring would increase the biological activity of this class. The conclusions of this work may lead to a better understanding of HIV-1 IN inhibition and contribute to the design of new and more potent derivatives. PMID:24039405

Computer-aided design of negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5): Comparative molecular field analysis of aryl ether derivatives.

PubMed

Selvam, Chelliah; Thilagavathi, Ramasamy; Narasimhan, Balasubramanian; Kumar, Pradeep; Jordan, Brian C; Ranganna, Kasturi

2016-02-15

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative molecular field analysis (CoMFA) was performed on 73 analogs of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities. Published by Elsevier Ltd.

The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

NASA Astrophysics Data System (ADS)

Jójárt, Balázs; Martinek, Tamás A.; Márki, Árpád

2005-05-01

Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated Δ G bind and the p K i values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q CoMFA 2 = 0.653, q CoMSA 2 = 0.630 and r pred,CoMFA 2 = 0.852 , r pred,CoMSIA 2 = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum.

PubMed

Thillainayagam, Mahalakshmi; Anbarasu, Anand; Ramaiah, Sudha

2016-08-21

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q(2)) of 0.912 and the non-cross-validated correlation coefficient (r(2)) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r(2) value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds. Copyright © 2016 Elsevier Ltd. All rights reserved.

New potent and selective cytochrome P450 2B6 (CYP2B6) inhibitors based on three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis

PubMed Central

Korhonen, L E; Turpeinen, M; Rahnasto, M; Wittekindt, C; Poso, A; Pelkonen, O; Raunio, H; Juvonen, R O

2007-01-01

Background and purpose: The cytochrome P450 2B6 (CYP2B6) enzyme metabolises a number of clinically important drugs. Drug-drug interactions resulting from inhibition or induction of CYP2B6 activity may cause serious adverse effects. The aims of this study were to construct a three-dimensional structure-activity relationship (3D-QSAR) model of the CYP2B6 protein and to identify novel potent and selective inhibitors of CYP2B6 for in vitro research purposes. Experimental approach: The inhibition potencies (IC50 values) of structurally diverse chemicals were determined with recombinant human CYP2B6 enzyme. Two successive models were constructed using Comparative Molecular Field Analysis (CoMFA). Key results: Three compounds proved to be very potent and selective competitive inhibitors of CYP2B6 in vitro (IC50<1 μM): 4-(4-chlorobenzyl)pyridine (CBP), 4-(4-nitrobenzyl)pyridine (NBP), and 4-benzylpyridine (BP). A complete inhibition of CYP2B6 activity was achieved with 0.1 μM CBP, whereas other CYP-related activities were not affected. Forty-one compounds were selected for further testing and construction of the final CoMFA model. The created CoMFA model was of high quality and predicted accurately the inhibition potency of a test set (n=7) of structurally diverse compounds. Conclusions and implications: Two CoMFA models were created which revealed the key molecular characteristics of inhibitors of the CYP2B6 enzyme. The final model accurately predicted the inhibitory potencies of several structurally unrelated compounds. CBP, BP and NBP were identified as novel potent and selective inhibitors of CYP2B6 and CBP especially is a suitable inhibitor for in vitro screening studies. PMID:17325652

An integrated molecular modeling approach for in silico design of new tetracyclic derivatives as ALK inhibitors.

PubMed

Peddi, Saikiran Reddy; Sivan, Sree Kanth; Manga, Vijjulatha

2016-10-01

Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.

Design, synthesis, pharmacological evaluation and in silico ADMET prediction of novel substituted benzimidazole derivatives as angiotensin II-AT1 receptor antagonists based on predictive 3D QSAR models.

PubMed

Vyas, V K; Gupta, N; Ghate, M; Patel, S

2014-01-01

In this study we designed novel substituted benzimidazole derivatives and predicted their absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, based on a predictive 3D QSAR study on 132 substituted benzimidazoles as AngII-AT1 receptor antagonists. The two best predicted compounds were synthesized and evaluated for AngII-AT1 receptor antagonism. Three different alignment tools for comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used. The best 3D QSAR models were obtained using the rigid body (Distill) alignment method. CoMFA and CoMSIA models were found to be statistically significant with leave-one-out correlation coefficients (q(2)) of 0.630 and 0.623, respectively, cross-validated coefficients (r(2)cv) of 0.651 and 0.630, respectively, and conventional coefficients of determination (r(2)) of 0.848 and 0.843, respectively. 3D QSAR models were validated using a test set of 24 compounds, giving satisfactory predicted results (r(2)pred) of 0.727 and 0.689 for the CoMFA and CoMSIA models, respectively. We have identified some key features in substituted benzimidazole derivatives, such as lipophilicity and H-bonding at the 2- and 5-positions of the benzimidazole nucleus, respectively, for AT1 receptor antagonistic activity. We designed 20 novel substituted benzimidazole derivatives and predicted their activity. In silico ADMET properties were also predicted for these designed molecules. Finally, the compounds with best predicted activity were synthesized and evaluated for in vitro angiotensin II-AT1 receptor antagonism.

Comparative molecular field analysis of fenoterol derivatives: A platform towards highly selective and effective beta(2)-adrenergic receptor agonists.

PubMed

Jozwiak, Krzysztof; Woo, Anthony Yiu-Ho; Tanga, Mary J; Toll, Lawrence; Jimenez, Lucita; Kozocas, Joseph A; Plazinska, Anita; Xiao, Rui-Ping; Wainer, Irving W

2010-01-15

To use a previously developed CoMFA model to design a series of new structures of high selectivity and efficacy towards the beta(2)-adrenergic receptor. Out of 21 computationally designed structures 6 compounds were synthesized and characterized for beta(2)-AR binding affinities, subtype selectivities and functional activities. the best compound is (R,R)-4-methoxy-1-naphthylfelnoterol with K(i)beta(2)-AR=0.28microm, K(i)beta(1)-AR/K(i)beta(2)-AR=573, EC(50cAMP)=3.9nm, EC(50cardio)=16nm. The CoMFA model appears to be an effective predictor of the cardiomocyte contractility of the studied compounds which are targeted for use in congestive heart failure. Copyright 2009 Elsevier Ltd. All rights reserved.

The synthesis, antimalarial activity and CoMFA analysis of novel aminoalkylated quercetin analogs.

PubMed

Helgren, Travis R; Sciotti, Richard J; Lee, Patricia; Duffy, Sandra; Avery, Vicky M; Igbinoba, Osayawemwen; Akoto, Matthew; Hagen, Timothy J

2015-01-15

A series of novel aminoalkylated quercetin analogs, prepared via the Mannich reaction of various primary and secondary amines with formaldehyde, were tested for antimalarial activity. The compounds were screened against three drug resistant malarial strains (D6, C235 and W2) and were found to exhibit sub-micromolar activity across all three strains (0.065-13.0μM). The structure-activity relationship determined from the antimalarial activity data suggests the inclusion of phenethyl amine sidechains on the quercetin scaffolding is necessary for potent activity. Additionally, the most active compounds ((5) and (6)) were tested for both early and late stage anti-gametocytocidal activity. Finally, the antimalarial activity data were utilized to construct comparative molecular field analysis (CoMFA) models to be used for further compound refinement. Copyright © 2014 Elqsevier Ltd. All rights reserved.

3D-QSAR, homology modeling, and molecular docking studies on spiropiperidines analogues as agonists of nociceptin/orphanin FQ receptor.

PubMed

Liu, Ming; He, Lin; Hu, Xiaopeng; Liu, Peiqing; Luo, Hai-Bin

2010-12-01

The nociceptin/orphanin FQ receptor (NOP) has been implicated in a wide range of biological functions, including pain, anxiety, depression and drug abuse. Especially, its agonists have a great potential to be developed into anxiolytics. However, the crystal structure of NOP is still not available. In the present work, both structure-based and ligand-based modeling methods have been used to achieve a comprehensive understanding on 67N-substituted spiropiperidine analogues as NOP agonists. The comparative molecular-field analysis method was performed to formulate a reasonable 3D-QSAR model (cross-validated coefficient q(2)=0.819 and conventional r(2)=0.950), whose robustness and predictability were further verified by leave-eight-out, Y-randomization, and external test-set validations. The excellent performance of CoMFA to the affinity differences among these compounds was attributed to the contributions of electrostatic/hydrogen-bonding and steric/hydrophobic interactions, which was supported by the Surflex-Dock and CDOCKER molecular-docking simulations based on the 3D model of NOP built by the homology modeling method. The CoMFA contour maps and the molecular docking simulations were integrated to propose a binding mode for the spiropiperidine analogues at the binding site of NOP. Copyright © 2010 Elsevier Ltd. All rights reserved.

3D-QSAR CoMFA of a series of DABO derivatives as HIV-1 reverse transcriptase non-nucleoside inhibitors.

PubMed

de Brito, Monique Araújo; Rodrigues, Carlos Rangel; Cirino, José Jair Vianna; de Alencastro, Ricardo Bicca; Castro, Helena Carla; Albuquerque, Magaly Girão

2008-08-01

A series of 74 dihydroalkoxybenzyloxopyrimidines (DABOs), a class of highly potent non-nucleoside reverse transcriptase inhibitors (NNRTIs), was retrieved from the literature and studied by comparative molecular field analysis (CoMFA) in order to derive three-dimensional quantitative structure-activity relationship (3D-QSAR) models. The CoMFA study has been performed with a training set of 59 compounds, testing three alignments and four charge schemes (DFT, HF, AM1, and PM3) and using defaults probe atom (Csp (3), +1 charge), cutoffs (30 kcal.mol (-1) for both steric and electrostatic fields), and grid distance (2.0 A). The best model ( N = 59), derived from Alignment 1 and PM3 charges, shows q (2) = 0.691, SE cv = 0.475, optimum number of components = 6, r (2) = 0.930, SEE = 0.226, and F-value = 115.544. The steric and electrostatic contributions for the best model were 43.2% and 56.8%, respectively. The external predictive ability (r (2) pred = 0.918) of the resultant best model was evaluated using a test set of 15 compounds. In order to design more potent DABO analogues as anti-HIV/AIDS agents, attention should be taken in order to select a substituent for the 4-oxopyrimidine ring, since, as revealed by the best CoMFA model, there are a steric restriction at the C2-position, a electron-rich group restriction at the C6-position ( para-substituent of the 6-benzyl group), and a steric allowed region at the C5-position.

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor.

PubMed

Chitta, Aparna; Jatavath, Mohan Babu; Fatima, Sabiha; Manga, Vijjulatha

2012-02-01

To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.

Binding site exploration of CCR5 using in silico methodologies: a 3D-QSAR approach.

PubMed

Gadhe, Changdev G; Kothandan, Gugan; Cho, Seung Joo

2013-01-01

Chemokine receptor 5 (CCR5) is an important receptor used by human immunodeficiency virus type 1 (HIV-1) to gain viral entry into host cell. In this study, we used a combined approach of comparative modeling, molecular docking, and three dimensional quantitative structure activity relationship (3D-QSAR) analyses to elucidate detailed interaction of CCR5 with their inhibitors. Docking study of the most potent inhibitor from a series of compounds was done to derive the bioactive conformation. Parameters such as random selection, rational selection, different charges and grid spacing were utilized in the model development to check their performance on the model predictivity. Final comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were chosen based on the rational selection method, Gasteiger-Hückel charges and a grid spacing of 0.5 Å. Rational model for CoMFA (q(2) = 0.722, r(2) = 0.884, Q(2) = 0.669) and CoMSIA (q(2) = 0.712, r(2) = 0.825, Q(2) = 0.522) was obtained with good statistics. Mapping of contour maps onto CCR5 interface led us to better understand of the ligand-protein interaction. Docking analysis revealed that the Glu283 is crucial for interaction. Two new amino acid residues, Tyr89 and Thr167 were identified as important in ligand-protein interaction. No site directed mutagenesis studies on these residues have been reported.

4D-LQTA-QSAR and docking study on potent Gram-negative specific LpxC inhibitors: a comparison to CoMFA modeling.

PubMed

Ghasemi, Jahan B; Safavi-Sohi, Reihaneh; Barbosa, Euzébio G

2012-02-01

A quasi 4D-QSAR has been carried out on a series of potent Gram-negative LpxC inhibitors. This approach makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package. This new methodology is based on the generation of a conformational ensemble profile, CEP, for each compound instead of only one conformation, followed by the calculation intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are independent variables employed in a QSAR analysis. The comparison of the proposed methodology to comparative molecular field analysis (CoMFA) formalism was performed. This methodology explores jointly the main features of CoMFA and 4D-QSAR models. Step-wise multiple linear regression was used for the selection of the most informative variables. After variable selection, multiple linear regression (MLR) and partial least squares (PLS) methods used for building the regression models. Leave-N-out cross-validation (LNO), and Y-randomization were performed in order to confirm the robustness of the model in addition to analysis of the independent test set. Best models provided the following statistics: [Formula in text] (PLS) and [Formula in text] (MLR). Docking study was applied to investigate the major interactions in protein-ligand complex with CDOCKER algorithm. Visualization of the descriptors of the best model helps us to interpret the model from the chemical point of view, supporting the applicability of this new approach in rational drug design.

Structure-Activity Relationships Based on 3D-QSAR CoMFA/CoMSIA and Design of Aryloxypropanol-Amine Agonists with Selectivity for the Human β3-Adrenergic Receptor and Anti-Obesity and Anti-Diabetic Profiles.

PubMed

Lorca, Marcos; Morales-Verdejo, Cesar; Vásquez-Velásquez, David; Andrades-Lagos, Juan; Campanini-Salinas, Javier; Soto-Delgado, Jorge; Recabarren-Gajardo, Gonzalo; Mella, Jaime

2018-05-16

The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r ² ncv = 0.993 and 0.984 and values of r ² test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation ( q ², r ², r ² m , etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC 50 = 8.561).

Prediction of octanol-air partition coefficients for polychlorinated biphenyls (PCBs) using 3D-QSAR models.

PubMed

Chen, Ying; Cai, Xiaoyu; Jiang, Long; Li, Yu

2016-02-01

Based on the experimental data of octanol-air partition coefficients (KOA) for 19 polychlorinated biphenyl (PCB) congeners, two types of QSAR methods, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), are used to establish 3D-QSAR models using the structural parameters as independent variables and using logKOA values as the dependent variable with the Sybyl software to predict the KOA values of the remaining 190 PCB congeners. The whole data set (19 compounds) was divided into a training set (15 compounds) for model generation and a test set (4 compounds) for model validation. As a result, the cross-validation correlation coefficient (q(2)) obtained by the CoMFA and CoMSIA models (shuffled 12 times) was in the range of 0.825-0.969 (>0.5), the correlation coefficient (r(2)) obtained was in the range of 0.957-1.000 (>0.9), and the SEP (standard error of prediction) of test set was within the range of 0.070-0.617, indicating that the models were robust and predictive. Randomly selected from a set of models, CoMFA analysis revealed that the corresponding percentages of the variance explained by steric and electrostatic fields were 23.9% and 76.1%, respectively, while CoMSIA analysis by steric, electrostatic and hydrophobic fields were 0.6%, 92.6%, and 6.8%, respectively. The electrostatic field was determined as a primary factor governing the logKOA. The correlation analysis of the relationship between the number of Cl atoms and the average logKOA values of PCBs indicated that logKOA values gradually increased as the number of Cl atoms increased. Simultaneously, related studies on PCB detection in the Arctic and Antarctic areas revealed that higher logKOA values indicate a stronger PCB migration ability. From CoMFA and CoMSIA contour maps, logKOA decreased when substituents possessed electropositive groups at the 2-, 3-, 3'-, 5- and 6- positions, which could reduce the PCB migration ability. These results are expected to be beneficial in predicting logKOA values of PCB homologues and derivatives and in providing a theoretical foundation for further elucidation of the global migration behaviour of PCBs. Copyright © 2015 Elsevier Inc. All rights reserved.

3D QSAR studies on binding affinities of coumarin natural products for glycosomal GAPDH of Trypanosoma cruzi

NASA Astrophysics Data System (ADS)

Menezes, Irwin R. A.; Lopes, Julio C. D.; Montanari, Carlos A.; Oliva, Glaucius; Pavão, Fernando; Castilho, Marcelo S.; Vieira, Paulo C.; Pupo, M.^onica T.

2003-05-01

Drug design strategies based on Comparative Molecular Field Analysis (CoMFA) have been used to predict the activity of new compounds. The major advantage of this approach is that it permits the analysis of a large number of quantitative descriptors and uses chemometric methods such as partial least squares (PLS) to correlate changes in bioactivity with changes in chemical structure. Because it is often difficult to rationalize all variables affecting the binding affinity of compounds using CoMFA solely, the program GRID was used to describe ligands in terms of their molecular interaction fields, MIFs. The program VolSurf that is able to compress the relevant information present in 3D maps into a few descriptors can treat these GRID fields. The binding affinities of a new set of compounds consisting of 13 coumarins, for one of which the three-dimensional ligand-enzyme bound structure is known, were studied. A final model based on the mentioned programs was independently validated by synthesizing and testing new coumarin derivatives. By relying on our knowledge of the real physical data (i.e., combining crystallographic and binding affinity results), it is also shown that ligand-based design agrees with structure-based design. The compound with the highest binding affinity was the coumarin chalepin, isolated from Rutaceae species, with an IC50 value of 55.5 μM towards the enzyme glyceraldehyde-3-phosphate dehydrogenase (gGAPDH) from glycosomes of the parasite Trypanosoma cruzi, the causative agent of Chagas' disease. The proposed models from GRID MIFs have revealed the importance of lipophilic interactions in modulating the inhibition, but without excluding the dependence on stereo-electronic properties as found from CoMFA fields.

Quantitative structure-activity relationship of organosulphur compounds as soybean 15-lipoxygenase inhibitors using CoMFA and CoMSIA.

PubMed

Caballero, Julio; Fernández, Michael; Coll, Deysma

2010-12-01

Three-dimensional quantitative structure-activity relationship studies were carried out on a series of 28 organosulphur compounds as 15-lipoxygenase inhibitors using comparative molecular field analysis and comparative molecular similarity indices analysis. Quantitative information on structure-activity relationships is provided for further rational development and direction of selective synthesis. All models were carried out over a training set including 22 compounds. The best comparative molecular field analysis model only included steric field and had a good Q² = 0.789. Comparative molecular similarity indices analysis overcame the comparative molecular field analysis results: the best comparative molecular similarity indices analysis model also only included steric field and had a Q² = 0.894. In addition, this model predicted adequately the compounds contained in the test set. Furthermore, plots of steric comparative molecular similarity indices analysis field allowed conclusions to be drawn for the choice of suitable inhibitors. In this sense, our model should prove useful in future 15-lipoxygenase inhibitor design studies. © 2010 John Wiley & Sons A/S.

Carbohydrate composition, viscosity, solubility, and sensory acceptance of sweetpotato- and maize-based complementary foods

PubMed Central

Amagloh, Francis Kweku; Mutukumira, Anthony N.; Brough, Louise; Weber, Janet L.; Hardacre, Allan; Coad, Jane

2013-01-01

Background Cereal-based complementary foods from non-malted ingredients form a relatively high viscous porridge. Therefore, excessive dilution, usually with water, is required to reduce the viscosity to be appropriate for infant feeding. The dilution invariably leads to energy and nutrient thinning, that is, the reduction of energy and nutrient densities. Carbohydrate is the major constituent of food that significantly influences viscosity when heated in water. Objectives To compare the sweetpotato-based complementary foods (extrusion-cooked ComFa, roller-dried ComFa, and oven-toasted ComFa) and enriched Weanimix (maize-based formulation) regarding their 1) carbohydrate composition, 2) viscosity and water solubility index (WSI), and 3) sensory acceptance evaluated by sub-Sahara African women as model caregivers. Methods The level of simple sugars/carbohydrates was analysed by spectrophotometry, total dietary fibre by enzymatic-gravimetric method, and total carbohydrate and starch levels estimated by calculation. A Rapid Visco™ Analyser was used to measure viscosity. WSI was determined gravimetrically. A consumer sensory evaluation was used to evaluate the product acceptance of the roller-dried ComFa, oven-toasted ComFa, and enriched Weanimix. Results The sweetpotato-based complementary foods were, on average, significantly higher in maltose, sucrose, free glucose and fructose, and total dietary fibre, but they were markedly lower in starch content compared with the levels in the enriched Weanimix. Consequently, the sweetpotato-based complementary foods had relatively low apparent viscosity, and high WSI, than that of enriched Weanimix. The scores of sensory liking given by the caregivers were highest for the roller-dried ComFa, followed by the oven-toasted ComFa, and, finally, the enriched Weanimix. Conclusion The sweetpotato-based formulations have significant advantages as complementary food due to the high level of endogenous sugars and low starch content that reduce the viscosity, increase the solubility, impart desirable sensory characteristics, and potentially avoid excessive energy and nutrient thinning. PMID:23516115

QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR

NASA Astrophysics Data System (ADS)

Zheng, Mingyue; Yu, Kunqian; Liu, Hong; Luo, Xiaomin; Chen, Kaixian; Zhu, Weiliang; Jiang, Hualiang

2006-09-01

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure-activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q 2 of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing novel potent NA inhibitors.

CoMFA, LeapFrog and blind docking studies on sulfonanilide derivatives acting as selective aromatase expression regulators.

PubMed

Gueto, Carlos; Torres, Juan; Vivas-Reyes, Ricardo

2009-09-01

Aromatase, the enzyme responsible for estrogen biosynthesis, is an attractive target in the treatment of hormone-dependent breast cancer. In this manuscript, the structure-based drug design approach of sulfonanilide analogues as potential selective aromatase expression regulators (SAERs) is described. Receptor-independent CoMFA (Comparative Molecular Field Analysis) maps were employed for generating a pseudocavity for LeapFrog calculation. A robust model, using 45 and 10 molecules in the training and test sets, respectively, was developed producing statistically significant results with cross-validated and conventional correlation coefficients of 0.656 and 0.956, respectively. This model was used to predict the activity of newly proposed molecules as SAERs candidates being two magnitude orders more potent than the previously reported compounds. Also in the present study, the computational blind docking method using eHiTS is tested on molecules study group and COX-2 enzyme. Future perspectives of the method in the screening of SAERs candidates with no COX-2 inhibitory activity are discussed.

Three-dimensional quantitative structure-property relationship (3D-QSPR) models for prediction of thermodynamic properties of polychlorinated biphenyls (PCBs): enthalpy of vaporization.

PubMed

Puri, Swati; Chickos, James S; Welsh, William J

2002-01-01

Three-dimensional Quantitative Structure-Property Relationship (QSPR) models have been derived using Comparative Molecular Field Analysis (CoMFA) to correlate the vaporization enthalpies of a representative set of polychlorinated biphenyls (PCBs) at 298.15 K with their CoMFA-calculated physicochemical properties. Various alignment schemes, such as inertial, as is, and atom fit, were employed in this study. The CoMFA models were also developed using different partial charge formalisms, namely, electrostatic potential (ESP) charges and Gasteiger-Marsili (GM) charges. The most predictive model for vaporization enthalpy (Delta(vap)H(m)(298.15 K)), with atom fit alignment and Gasteiger-Marsili charges, yielded r2 values 0.852 (cross-validated) and 0.996 (conventional). The vaporization enthalpies of PCBs increased with the number of chlorine atoms and were found to be larger for the meta- and para-substituted isomers. This model was used to predict Delta(vap)H(m)(298.15 K) of the entire set of 209 PCB congeners.

3D QSAR studies on protein tyrosine phosphatase 1B inhibitors: comparison of the quality and predictivity among 3D QSAR models obtained from different conformer-based alignments.

PubMed

Pandey, Gyanendra; Saxena, Anil K

2006-01-01

A set of 65 flexible peptidomimetic competitive inhibitors (52 in the training set and 13 in the test set) of protein tyrosine phosphatase 1B (PTP1B) has been used to compare the quality and predictive power of 3D quantitative structure-activity relationship (QSAR) comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for the three most commonly used conformer-based alignments, namely, cocrystallized conformer-based alignment (CCBA), docked conformer-based alignment (DCBA), and global minima energy conformer-based alignment (GMCBA). These three conformers of 5-[(2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)3-oxo-3-pentylamino)propyl]-2-(carboxymethoxy)benzoic acid (compound number 66) were obtained from the X-ray structure of its cocrystallized complex with PTP1B (PDB ID: 1JF7), its docking studies, and its global minima by simulated annealing. Among the 3D QSAR models developed using the above three alignments, the CCBA provided the optimal predictive CoMFA model for the training set with cross-validated r2 (q2)=0.708, non-cross-validated r2=0.902, standard error of estimate (s)=0.165, and F=202.553 and the optimal CoMSIA model with q2=0.440, r2=0.799, s=0.192, and F=117.782. These models also showed the best test set prediction for the 13 compounds with predictive r2 values of 0.706 and 0.683, respectively. Though the QSAR models derived using the other two alignments also produced statistically acceptable models in the order DCBA>GMCBA in terms of the values of q2, r2, and predictive r2, they were inferior to the corresponding models derived using CCBA. Thus, the order of preference for the alignment selection for 3D QSAR model development may be CCBA>DCBA>GMCBA, and the information obtained from the CoMFA and CoMSIA contour maps may be useful in designing specific PTP1B inhibitors.

Study on the activity of non-purine xanthine oxidase inhibitor by 3D-QSAR modeling and molecular docking

NASA Astrophysics Data System (ADS)

Li, Peizhen; Tian, Yueli; Zhai, Honglin; Deng, Fangfang; Xie, Meihong; Zhang, Xiaoyun

2013-11-01

Non-purine derivatives have been shown to be promising novel drug candidates as xanthine oxidase inhibitors. Based on three-dimensional quantitative structure-activity relationship (3D-QSAR) methods including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), two 3D-QSAR models for a series of non-purine xanthine oxidase (XO) inhibitors were established, and their reliability was supported by statistical parameters. Combined 3D-QSAR modeling and the results of molecular docking between non-purine xanthine oxidase inhibitors and XO, the main factors that influenced activity of inhibitors were investigated, and the obtained results could explain known experimental facts. Furthermore, several new potential inhibitors with higher activity predicted were designed, which based on our analyses, and were supported by the simulation of molecular docking. This study provided some useful information for the development of non-purine xanthine oxidase inhibitors with novel structures.

Molecular design of new aggrecanases-2 inhibitors.

PubMed

Shan, Zhi Jie; Zhai, Hong Lin; Huang, Xiao Yan; Li, Li Na; Zhang, Xiao Yun

2013-10-01

Aggrecanases-2 is a very important potential drug target for the treatment of osteoarthritis. In this study, a series of known aggrecanases-2 inhibitors was analyzed by the technologies of three-dimensional quantitative structure-activity relationships (3D-QSAR) and molecular docking. Two 3D-QSAR models, which based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods, were established. Molecular docking was employed to explore the details of the interaction between inhibitors and aggrecanases-2 protein. According to the analyses for these models, several new potential inhibitors with higher activity predicted were designed, and were supported by the simulation of molecular docking. This work propose the fast and effective approach to design and prediction for new potential inhibitors, and the study of the interaction mechanism provide a better understanding for the inhibitors binding into the target protein, which will be useful for the structure-based drug design and modifications. Copyright © 2013 Elsevier Ltd. All rights reserved.

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations

PubMed Central

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-01-01

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q2 (cross-validated correlation coefficient) = 0.557, R2ncv (non-cross-validated correlation coefficient) = 0.740, R2pre (predicted correlation coefficient) = 0.749 and Q2 = 0.598, R2ncv = 0.767, R2pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors. PMID:26307982

Insight into the Structural Determinants of Imidazole Scaffold-Based Derivatives as TNF-α Release Inhibitors by in Silico Explorations.

PubMed

Wang, Yuan; Wu, Mingwei; Ai, Chunzhi; Wang, Yonghua

2015-08-25

Presently, 151 widely-diverse pyridinylimidazole-based compounds that show inhibitory activities at the TNF-α release were investigated. By using the distance comparison technique (DISCOtech), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) methods, the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds were explored. The proposed pharmacophore model, including two hydrophobic sites, two aromatic centers, two H-bond donor atoms, two H-bond acceptor atoms, and two H-bond donor sites characterizes the necessary structural features of TNF-α release inhibitors. Both the resultant CoMFA and CoMSIA models exhibited satisfactory predictability (with Q(2) (cross-validated correlation coefficient) = 0.557, R(2)ncv (non-cross-validated correlation coefficient) = 0.740, R(2)pre (predicted correlation coefficient) = 0.749 and Q(2) = 0.598, R(2)ncv = 0.767, R(2)pre = 0.860, respectively). Good consistency was observed between the 3D-QSAR models and the pharmacophore model that the hydrophobic interaction and hydrogen bonds play crucial roles in the mechanism of actions. The corresponding contour maps generated by these models provide more diverse information about the key intermolecular interactions of inhibitors with the surrounding environment. All these models have extended the understanding of imidazole-based compounds in the structure-activity relationship, and are useful for rational design and screening of novel 2-thioimidazole-based TNF-α release inhibitors.

Iron Bioavailability and Provitamin A from Sweet Potato- and Cereal-Based Complementary Foods

PubMed Central

Christides, Tatiana; Amagloh, Francis Kweku; Coad, Jane

2015-01-01

Iron and vitamin A deficiencies in childhood are public health problems in the developing world. Introduction of cereal-based complementary foods, that are often poor sources of both vitamin A and bioavailable iron, increases the risk of deficiency in young children. Alternative foods with higher levels of vitamin A and bioavailable iron could help alleviate these micronutrient deficiencies. The objective of this study was to compare iron bioavailability of β-carotene-rich sweet potato-based complementary foods (orange-flesh based sweet potato (OFSP) ComFa and cream-flesh sweet potato based (CFSP) ComFa with a household cereal-based complementary food (Weanimix) and a commercial cereal (Cerelac®), using the in vitro digestion/Caco-2 cell model. Iron bioavailability relative to total iron, concentrations of iron-uptake inhibitors (fibre, phytates, and polyphenols), and enhancers (ascorbic acid, ß-carotene and fructose) was also evaluated. All foods contained similar amounts of iron, but bioavailability varied: Cerelac® had the highest, followed by OFSP ComFa and Weanimix, which had equivalent bioavailable iron; CFSP ComFa had the lowest bioavailability. The high iron bioavailability from Cerelac® was associated with the highest levels of ascorbic acid, and the lowest levels of inhibitors; polyphenols appeared to limit sweet potato-based food iron bioavailability. Taken together, the results do not support that CFSP- and OFSP ComFa are better sources of bioavailable iron compared with non-commercial/household cereal-based weaning foods; however, they may be a good source of provitamin A in the form of β-carotene. PMID:28231217

Investigating the binding mechanism of novel 6-aminonicotinate-based antagonists with P2Y12 by 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Zhou, Shengfu; Fang, Danqing; Tan, Shepei; Lin, Weicong; Wu, Wenjuan; Zheng, Kangcheng

2017-10-01

P2Y 12 receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y 12 antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y 12 and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R 2  = .983, q 2  = .805, [Formula: see text] = .881 for CoMFA model, and R 2  = .935, q 2  = .762, [Formula: see text] = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y 12 . We hope these results could be helpful in design of potent and selective P2Y 12 antagonists.

Studies of New Fused Benzazepine as Selective Dopamine D3 Receptor Antagonists Using 3D-QSAR, Molecular Docking and Molecular Dynamics

PubMed Central

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-01-01

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q2 = 0.603, R2ncv = 0.829, R2pre = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q2 = 0.506, R2ncv =0.838, R2pre = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R3 substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R1 substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists. PMID:21541053

Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

PubMed

Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

2011-02-18

In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

QSAR and 3D QSAR of inhibitors of the epidermal growth factor receptor

NASA Astrophysics Data System (ADS)

Pinto-Bazurco, Mariano; Tsakovska, Ivanka; Pajeva, Ilza

This article reports quantitative structure-activity relationships (QSAR) and 3D QSAR models of 134 structurally diverse inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase. Free-Wilson analysis was used to derive the QSAR model. It identified the substituents in aniline, the polycyclic system, and the substituents at the 6- and 7-positions of the polycyclic system as the most important structural features. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used in the 3D QSAR modeling. The steric and electrostatic interactions proved the most important for the inhibitory effect. Both QSAR and 3D QSAR models led to consistent results. On the basis of the statistically significant models, new structures were proposed and their inhibitory activities were predicted.

Interactions between cycloguanil derivatives and wild type and resistance-associated mutant Plasmodium falciparum dihydrofolate reductases

NASA Astrophysics Data System (ADS)

Maitarad, Phornphimon; Kamchonwongpaisan, Sumalee; Vanichtanankul, Jarunee; Vilaivan, Tirayut; Yuthavong, Yongyuth; Hannongbua, Supa

2009-04-01

Comparative molecular field analysis (CoMFA) and quantum chemical calculations were performed on cycloguanil (Cyc) derivatives of the wild type and the quadruple mutant (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) of Plasmodium falciparum dihydrofolate reductase ( PfDHFR). The represented CoMFA models of wild type ( r_{{cv}}2 = 0.727 and r 2 = 0.985) and mutant type ( r_{{cv}}2 = 0.786 and r 2 = 0.979) can describe the differences of the Cyc structural requirements for the two types of PfDHFR enzymes and can be useful to guide the design of new inhibitors. Moreover, the obtained particular interaction energies between the Cyc and the surrounding residues in the binding pocket indicated that Asn108 of mutant enzyme was the cause of Cyc resistance by producing steric clash with p-Cl of Cyc. Consequently, comparing the energy contributions with the potent flexible WR99210 inhibitor, it was found that the key mutant residue, Asn108, demonstrates attractive interaction with this inhibitor and some residues, Leu46, Ile112, Pro113, Phe116, and Leu119, seem to perform as second binding site with WR99210. Therefore, quantum chemical calculations can be useful for investigating residue interactions to clarify the cause of drug resistance.

Quantitative structure activity relationship studies of mushroom tyrosinase inhibitors

NASA Astrophysics Data System (ADS)

Xue, Chao-Bin; Luo, Wan-Chun; Ding, Qi; Liu, Shou-Zhu; Gao, Xing-Xiang

2008-05-01

Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between benzoic acid derivatives and the tyrosinase active site is the formation of a hydrogen-bond between the hydroxyl (aOH) and carbonyl oxygen atoms of Tyr98, which stabilized the position of Tyr98 and prevented Tyr98 from participating in the interaction between tyrosinase and ORF378. Tyrosinase, also known as phenoloxidase, is a key enzyme in animals, plants and insects that is responsible for catalyzing the hydroxylation of tyrosine into o-diphenols and the oxidation of o-diphenols into o-quinones. In the present study, the bioactivities of 48 derivatives of benzaldehyde, benzoic acid, and cinnamic acid compounds were used to construct three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field (CoMFA) and comparative molecular similarity indices (CoMSIA) analyses. After superimposition using common substructure-based alignments, robust and predictive 3D-QSAR models were obtained from CoMFA ( q 2 = 0.855, r 2 = 0.978) and CoMSIA ( q 2 = 0.841, r 2 = 0.946), with 6 optimum components. Chemical descriptors, including electronic (Hammett σ), hydrophobic (π), and steric (MR) parameters, hydrogen bond acceptor (H-acc), and indicator variable ( I), were used to construct a 2D-QSAR model. The results of this QSAR indicated that π, MR, and H-acc account for 34.9, 31.6, and 26.7% of the calculated biological variance, respectively. The molecular interactions between ligand and target were studied using a flexible docking method (FlexX). The best scored candidates were docked flexibly, and the interaction between the benzoic acid derivatives and the tyrosinase active site was elucidated in detail. We believe that the QSAR models built here provide important information necessary for the design of novel tyrosinase inhibitors.

3D-QSAR and molecular docking study on bisarylmaleimide series as glycogen synthase kinase 3, cyclin dependent kinase 2 and cyclin dependent kinase 4 inhibitors: an insight into the criteria for selectivity.

PubMed

Dessalew, Nigus; Bharatam, Prasad V

2007-07-01

Selective glycogen synthase kinase 3 (GSK3) inhibition over cyclin dependent kinases such as cyclin dependent kinase 2 (CDK2) and cyclin dependent kinase 4 (CDK4) is an important requirement for improved therapeutic profile of GSK3 inhibitors. The concepts of selectivity and additivity fields have been employed in developing selective CoMFA models for these related kinases. Initially, sets of three individual CoMFA models were developed, using 36 compounds of bisarylmaleimide series to correlate with the GSK3, CDK2 and CDK4 inhibitory potencies. These models showed a satisfactory statistical significance: CoMFA-GSK3 (r(2)(con), r(2)(cv): 0.931, 0.519), CoMFA-CDK2 (0.937, 0.563), and CoMFA-CDK4 (0.892, 0.725). Three different selective CoMFA models were then developed using differences in pIC(50) values. These three models showed a superior statistical significance: (i) CoMFA-Selective1 (r(2)(con), r(2)(cv): 0.969, 0.768), (ii) CoMFA-Selective 2 (0.974, 0.835) and (iii) CoMFA-Selective3 (0.963, 0.776). The selective models were found to outperform the individual models in terms of the quality of correlation and were found to be more informative in pinpointing the structural basis for the observed quantitative differences of kinase inhibition. An in-depth comparative investigation was carried out between the individual and selective models to gain an insight into the selectivity criterion. To further validate this approach, a set of new compounds were designed which show selectivity and were docked into the active site of GSK3, using FlexX based incremental construction algorithm.

Three-dimensional quantitative structure-activity relationship (3D QSAR) and pharmacophore elucidation of tetrahydropyran derivatives as serotonin and norepinephrine transporter inhibitors

NASA Astrophysics Data System (ADS)

Kharkar, Prashant S.; Reith, Maarten E. A.; Dutta, Aloke K.

2008-01-01

Three-dimensional quantitative structure-activity relationship (3D QSAR) using comparative molecular field analysis (CoMFA) was performed on a series of substituted tetrahydropyran (THP) derivatives possessing serotonin (SERT) and norepinephrine (NET) transporter inhibitory activities. The study aimed to rationalize the potency of these inhibitors for SERT and NET as well as the observed selectivity differences for NET over SERT. The dataset consisted of 29 molecules, of which 23 molecules were used as the training set for deriving CoMFA models for SERT and NET uptake inhibitory activities. Superimpositions were performed using atom-based fitting and 3-point pharmacophore-based alignment. Two charge calculation methods, Gasteiger-Hückel and semiempirical PM3, were tried. Both alignment methods were analyzed in terms of their predictive abilities and produced comparable results with high internal and external predictivities. The models obtained using the 3-point pharmacophore-based alignment outperformed the models with atom-based fitting in terms of relevant statistics and interpretability of the generated contour maps. Steric fields dominated electrostatic fields in terms of contribution. The selectivity analysis (NET over SERT), though yielded models with good internal predictivity, showed very poor external test set predictions. The analysis was repeated with 24 molecules after systematically excluding so-called outliers (5 out of 29) from the model derivation process. The resulting CoMFA model using the atom-based fitting exhibited good statistics and was able to explain most of the selectivity (NET over SERT)-discriminating factors. The presence of -OH substituent on the THP ring was found to be one of the most important factors governing the NET selectivity over SERT. Thus, a 4-point NET-selective pharmacophore, after introducing this newly found H-bond donor/acceptor feature in addition to the initial 3-point pharmacophore, was proposed.

Analyzing the substitution effect on the CoMFA results within the framework of density functional theory (DFT).

PubMed

Morales-Bayuelo, Alejandro

2016-07-01

Though QSAR was originally developed in the context of physical organic chemistry, it has been applied very extensively to chemicals (drugs) which act on biological systems, in this idea one of the most important QSAR methods is the 3D QSAR model. However, due to the complexity of understanding the results it is necessary to postulate new methodologies to highlight their physical-chemical meaning. In this sense, this work postulates new insights to understand the CoMFA results using molecular quantum similarity and chemical reactivity descriptors within the framework of density functional theory. To obtain these insights a simple theoretical scheme involving quantum similarity (overlap, coulomb operators, their euclidean distances) and chemical reactivity descriptors such as chemical potential (μ), hardness (ɳ), softness (S), electrophilicity (ω), and the Fukui functions, was used to understand the substitution effect. In this sense, this methodology can be applied to analyze the biological activity and the stabilization process in the non-covalent interactions on a particular molecular set taking a reference compound.

A Conserved Metal Binding Motif in the Bacillus subtilis Competence Protein ComFA Enhances Transformation.

PubMed

Chilton, Scott S; Falbel, Tanya G; Hromada, Susan; Burton, Briana M

2017-08-01

Genetic competence is a process in which cells are able to take up DNA from their environment, resulting in horizontal gene transfer, a major mechanism for generating diversity in bacteria. Many bacteria carry homologs of the central DNA uptake machinery that has been well characterized in Bacillus subtilis It has been postulated that the B. subtilis competence helicase ComFA belongs to the DEAD box family of helicases/translocases. Here, we made a series of mutants to analyze conserved amino acid motifs in several regions of B. subtilis ComFA. First, we confirmed that ComFA activity requires amino acid residues conserved among the DEAD box helicases, and second, we show that a zinc finger-like motif consisting of four cysteines is required for efficient transformation. Each cysteine in the motif is important, and mutation of at least two of the cysteines dramatically reduces transformation efficiency. Further, combining multiple cysteine mutations with the helicase mutations shows an additive phenotype. Our results suggest that the helicase and metal binding functions are two distinct activities important for ComFA function during transformation. IMPORTANCE ComFA is a highly conserved protein that has a role in DNA uptake during natural competence, a mechanism for horizontal gene transfer observed in many bacteria. Investigation of the details of the DNA uptake mechanism is important for understanding the ways in which bacteria gain new traits from their environment, such as drug resistance. To dissect the role of ComFA in the DNA uptake machinery, we introduced point mutations into several motifs in the protein sequence. We demonstrate that several amino acid motifs conserved among ComFA proteins are important for efficient transformation. This report is the first to demonstrate the functional requirement of an amino-terminal cysteine motif in ComFA. Copyright © 2017 American Society for Microbiology.

Design, synthesis, antiviral activity and three-dimensional quantitative structure-activity relationship study of novel 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety.

PubMed

Gan, Xiuhai; Hu, Deyu; Li, Pei; Wu, Jian; Chen, Xuewen; Xue, Wei; Song, Baoan

2016-03-01

1,4-Pentadien-3-one and 1,3,4-oxadiazole derivatives possess good antiviral activities, and their substructure units are usually used in antiviral agent design. In order to discover novel molecules with high antiviral activities, a series of 1,4-pentadien-3-one derivatives containing the 1,3,4-oxadiazole moiety were designed and synthesised. Bioassays showed that most of the title compounds exhibited good inhibitory activities against tobacco mosaic virus (TMV) in vivo. The compound 8f possessing the best protective activity against TMV had an EC50 value of 135.56 mg L(-1) , which was superior to that of ribavirin (435.99 mg L(-1) ). Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were used in three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of protective activities, with values of q(2) and r(2) for the CoMFA and CoMSIA models of 0.751 and 0.775 and 0.936 and 0.925 respectively. Compound 8k with higher protective activity (EC50 = 123.53 mg L(-1) ) according to bioassay was designed and synthesised on the basis of the 3D-QSAR models. Some of the title compounds displayed good antiviral activities. 3D-QSAR models revealed that the appropriate compact electron-withdrawing and hydrophobic group at the benzene ring could enhance antiviral activity. These results could provide important structural insights for the design of highly active 1,4-pentadien-3-one derivatives. © 2015 Society of Chemical Industry.

Comparative molecular field analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β₂-adrenergic receptor.

PubMed

Plazinska, Anita; Pajak, Karolina; Rutkowska, Ewelina; Jimenez, Lucita; Kozocas, Joseph; Koolpe, Gary; Tanga, Mary; Toll, Lawrence; Wainer, Irving W; Jozwiak, Krzysztof

2014-01-01

The β₂-adrenergic receptor (β₂-AR) agonist [(3)H]-(R,R')-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4'-methoxyfenoterol analogs in which the length of the alkyl substituent at α' position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [(3)H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC₅₀ values, were determined in HEK293 cells expressing the β₂-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α' position. The results also indicate that the Ki values obtained using [(3)H]-(R,R')-methoxyfenoterol as the marker ligand modeled the EC₅₀ values obtained from cAMP stimulation better than the data obtained using [(3)H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β₂-AR conformation probed by [(3)H]-(R,R')-4'-methoxyfenoterol. The CoMFA model of the agonist-stabilized β₂-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β₂-AR is governed to a greater extend by steric effects than binding to the [(3)H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparative Molecular Field Analysis of fenoterol derivatives interacting with an agonist-stabilized form of the β2-adrenergic receptor

PubMed Central

Plazinska, Anita; Pajak, Karolina; Rutkowska, Ewelina; Jimenez, Lucita; Kozocas, Joseph; Koolpe, Gary; Tanga, Mary; Toll, Lawrence; Wainer, Irving W.; Jozwiak, Krzysztof

2014-01-01

The β2-adrenergic receptor (β2-AR) agonist [3H]-(R,R′)-methoxyfenoterol was employed as the marker ligand in displacement studies measuring the binding affinities (Ki values) of the stereoisomers of a series of 4′-methoxyfenoterol analogs in which the length of the alkyl substituent at α′ position was varied from 0 to 3 carbon atoms. The binding affinities of the compounds were additionally determined using the inverse agonist [3H]-CGP-12177 as the marker ligand and the ability of the compounds to stimulate cAMP accumulation, measured as EC50 values, were determined in HEK293 cells expressing the β2-AR. The data indicate that the highest binding affinities and functional activities were produced by methyl and ethyl substituents at the α′ position. The results also indicate that the Ki values obtained using [3H]-(R,R′)-methoxyfenoterol as the marker ligand modeled the EC50 values obtained from cAMP stimulation better than the data obtained using [3H]-CGP-12177 as the marker ligand. The data from this study was combined with data from previous studies and processed using the Comparative Molecular Field Analysis approach to produce a CoMFA model reflecting the binding to the β2-AR conformation probed by [3H]-(R,R′)-4′-methoxyfenoterol. The CoMFA model of the agonist-stabilized β2-AR suggests that the binding of the fenoterol analogs to an agonist-stabilized conformation of the β2-AR is governed to a greater extend by steric effects than binding to the [3H]-CGP-12177-stabilized conformation(s) in which electrostatic interactions play a more predominate role. PMID:24326276

Synthesis, fungicidal evaluation and 3D-QSAR studies of novel 1,3,4-thiadiazole xylofuranose derivatives

PubMed Central

Zong, Guanghui; Yan, Xiaojing; Bi, Jiawei; Jiang, Rui; Qin, Yinan; Yuan, Huizhu; Lu, Huizhe; Dong, Yanhong; Jin, Shuhui; Zhang, Jianjun

2017-01-01

1,3,4-Thiadiazole and sugar-derived molecules have proven to be promising agrochemicals with growth promoting, insecticidal and fungicidal activities. In the research field of agricultural fungicide, applying union of active group we synthesized a new set of 1,3,4-thiadiazole xylofuranose derivatives and all of the compounds were characterized by 1H NMR and HRMS. In precise toxicity measurement, some of compounds exhibited more potent fungicidal activities than the most widely used commercial fungicide Chlorothalonil, promoting further research and development. Based on our experimental data, 3D-QSAR (three-dimensional quantitative structure-activity relationship) was established and investigated using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques, helping to better understand the structural requirements of lead compounds with high fungicidal activity and environmental compatibility. PMID:28746366

3D-QSAR analysis of MCD inhibitors by CoMFA and CoMSIA.

PubMed

Pourbasheer, Eslam; Aalizadeh, Reza; Ebadi, Amin; Ganjali, Mohammad Reza

2015-01-01

Three-dimensional quantitative structure-activity relationship was developed for the series of compounds as malonyl-CoA decarboxylase antagonists (MCD) using the CoMFA and CoMSIA methods. The statistical parameters for CoMFA (q(2)=0.558, r(2)=0.841) and CoMSIA (q(2)= 0.615, r(2) = 0.870) models were derived based on 38 compounds as training set in the basis of the selected alignment. The external predictive abilities of the built models were evaluated by using the test set of nine compounds. From obtained results, the CoMSIA method was found to have highly predictive capability in comparison with CoMFA method. Based on the given results by CoMSIA and CoMFA contour maps, some features that can enhance the activity of compounds as MCD antagonists were introduced and used to design new compounds with better inhibition activity.

Ligand-based 3D QSAR analysis of reactivation potency of mono- and bis-pyridinium aldoximes toward VX-inhibited rat acetylcholinesterase.

PubMed

Dolezal, Rafael; Korabecny, Jan; Malinak, David; Honegr, Jan; Musilek, Kamil; Kuca, Kamil

2015-03-01

To predict unknown reactivation potencies of 12 mono- and bis-pyridinium aldoximes for VX-inhibited rat acetylcholinesterase (rAChE), three-dimensional quantitative structure-activity relationship (3D QSAR) analysis has been carried out. Utilizing molecular interaction fields (MIFs) calculated by molecular mechanical (MMFF94) and quantum chemical (B3LYP/6-31G*) methods, two satisfactory ligand-based CoMFA models have been developed: 1. R(2)=0.9989, Q(LOO)(2)=0.9090, Q(LTO)(2)=0.8921, Q(LMO(20%))(2)=0.8853, R(ext)(2)=0.9259, SDEP(ext)=6.8938; 2. R(2)=0.9962, Q(LOO)(2)=0.9368, Q(LTO)(2)=0.9298, Q(LMO(20%))(2)=0.9248, R(ext)(2)=0.8905, SDEP(ext)=6.6756. High statistical significance of the 3D QSAR models has been achieved through the application of several data noise reduction techniques (i.e. smart region definition SRD, fractional factor design FFD, uninformative/iterative variable elimination UVE/IVE) on the original MIFs. Besides the ligand-based CoMFA models, an alignment molecular set constructed by flexible molecular docking has been also studied. The contour maps as well as the predicted reactivation potencies resulting from 3D QSAR analyses help better understand which structural features are associated with increased reactivation potency of studied compounds. Copyright © 2014 Elsevier Inc. All rights reserved.

3D-QSPR Method of Computational Technique Applied on Red Reactive Dyes by Using CoMFA Strategy

PubMed Central

Mahmood, Uzma; Rashid, Sitara; Ali, S. Ishrat; Parveen, Rasheeda; Zaheer-ul-Haq; Ambreen, Nida; Khan, Khalid Mohammed; Perveen, Shahnaz; Voelter, Wolfgang

2011-01-01

Cellulose fiber is a tremendous natural resource that has broad application in various productions including the textile industry. The dyes, which are commonly used for cellulose printing, are “reactive dyes” because of their high wet fastness and brilliant colors. The interaction of various dyes with the cellulose fiber depends upon the physiochemical properties that are governed by specific features of the dye molecule. The binding pattern of the reactive dye with cellulose fiber is called the ligand-receptor concept. In the current study, the three dimensional quantitative structure property relationship (3D-QSPR) technique was applied to understand the red reactive dyes interactions with the cellulose by the Comparative Molecular Field Analysis (CoMFA) method. This method was successfully utilized to predict a reliable model. The predicted model gives satisfactory statistical results and in the light of these, it was further analyzed. Additionally, the graphical outcomes (contour maps) help us to understand the modification pattern and to correlate the structural changes with respect to the absorptivity. Furthermore, the final selected model has potential to assist in understanding the charachteristics of the external test set. The study could be helpful to design new reactive dyes with better affinity and selectivity for the cellulose fiber. PMID:22272108

Part A: Assessing the performance of the COMFA outdoor thermal comfort model on subjects performing physical activity

NASA Astrophysics Data System (ADS)

Kenny, Natasha A.; Warland, Jon S.; Brown, Robert D.; Gillespie, Terry G.

2009-09-01

This study assessed the performance of the COMFA outdoor thermal comfort model on subjects performing moderate to vigorous physical activity. Field tests were conducted on 27 subjects performing 30 min of steady-state activity (walking, running, and cycling) in an outdoor environment. The predicted COMFA budgets were compared to the actual thermal sensation (ATS) votes provided by participants during each 5-min interval. The results revealed a normal distribution in the subjects’ ATS votes, with 82% of votes received in categories 0 (neutral) to +2 (warm). The ATS votes were significantly dependent upon sex, air temperature, short and long-wave radiation, wind speed, and metabolic activity rate. There was a significant positive correlation between the ATS and predicted budgets (Spearman’s rho = 0.574, P < 0.01). However, the predicted budgets did not display a normal distribution, and the model produced erroneous estimates of the heat and moisture exchange between the human body and the ambient environment in 6% of the cases.

Three-dimensional structure-activity relationship modeling of cocaine binding to two monoclonal antibodies by comparative molecular field analysis.

PubMed

Paula, Stefan; Tabet, Michael R; Keenan, Susan M; Welsh, William J; Ball, W James

2003-01-17

Successful immunotherapy of cocaine addiction and overdoses requires cocaine-binding antibodies with specific properties, such as high affinity and selectivity for cocaine. We have determined the affinities of two cocaine-binding murine monoclonal antibodies (mAb: clones 3P1A6 and MM0240PA) for cocaine and its metabolites by [3H]-radioligand binding assays. mAb 3P1A6 (K(d) = 0.22 nM) displayed a 50-fold higher affinity for cocaine than mAb MM0240PA (K(d) = 11 nM) and also had a greater specificity for cocaine. For the systematic exploration of both antibodies' binding specificities, we used a set of approximately 35 cocaine analogues as structural probes by determining their relative binding affinities (RBAs) using an enzyme-linked immunosorbent competition assay. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models on the basis of comparative molecular field analysis (CoMFA) techniques correlated the binding data with structural features of the ligands. The analysis indicated that despite the mAbs' differing specificities for cocaine, the relative contributions of the steric (approximately 80%) and electrostatic (approximately 20%) field interactions to ligand-binding were similar. Generated three-dimensional CoMFA contour plots then located the specific regions about cocaine where the ligand/receptor interactions occurred. While the overall binding patterns of the two mAbs had many features in common, distinct differences were observed about the phenyl ring and the methylester group of cocaine. Furthermore, using previously published data, a 3D-QSAR model was developed for cocaine binding to the dopamine reuptake transporter (DAT) that was compared to the mAb models. Although the relative steric and electrostatic field contributions were similar to those of the mAbs, the DAT cocaine-binding site showed a preference for negatively charged ligands. Besides establishing molecular level insight into the interactions that govern cocaine binding specificity by biopolymers, the three-dimensional images obtained reflect the properties of the mAbs binding pockets and provide the initial information needed for the possible design of novel antibodies with properties optimized for immunotherapy. Copyright 2003 Elsevier Science Ltd.

Quantitative structure-activity relationship studies of threo-methylphenidate analogs.

PubMed

Misra, Milind; Shi, Qing; Ye, Xiaocong; Gruszecka-Kowalik, Ewa; Bu, Wei; Liu, Zhanzhu; Schweri, Margaret M; Deutsch, Howard M; Venanzi, Carol A

2010-10-15

Complementary two-dimensional (2D) and three-dimensional (3D) Quantitative Structure-Activity Relationship (QSAR) techniques were used to derive a preliminary model for the dopamine transporter (DAT) binding affinity of 80 racemic threo-methylphenidate (MP) analogs. A novel approach based on using the atom-level E-state indices of the 14 common scaffold atoms in a sphere exclusion protocol was used to identify a test set for 2D- and 3D-QSAR model validation. Comparative Molecular Field Analysis (CoMFA) contour maps based on the structure-activity data of the training set indicate that the 2' position of the phenyl ring cannot tolerate much steric bulk and that addition of electron-withdrawing groups to the 3' or 4' positions of the phenyl ring leads to improved DAT binding affinity. In particular, the optimal substituents were found to be those whose bulk is mainly in the plane of the phenyl ring. Substituents with significant bulk above or below the plane of the ring led to decreased binding affinity. Suggested alterations to be explored in the design of new compounds are the placement at the 3' and 4' position of the phenyl ring of electron-withdrawing groups that lie chiefly in the plane of the ring, for example, halogen substituents on the 3',4'-benzo analog, 79. A complementary 2D-QSAR approach-partial least squares analysis using a reduced set of Molconn-Z descriptors-supports the CoMFA structure-activity interpretation that phenyl ring substitution is a major determinant of DAT binding affinity. The potential usefulness of the CoMFA models was demonstrated by the prediction of the binding affinity of methyl 2-(naphthalen-1-yl)-2-(piperidin-2-yl)acetate, an analog not in the original data set, to be in good agreement with the experimental value. Copyright © 2010 Elsevier Ltd. All rights reserved.

CoMFA and CoMSIA 3D-QSAR studies on S(6)-(4-nitrobenzyl)mercaptopurine riboside (NBMPR) analogs as inhibitors of human equilibrative nucleoside transporter 1 (hENT1).

PubMed

Gupte, Amol; Buolamwini, John K

2009-01-15

3D-QSAR (CoMFA and CoMSIA) studies were performed on human equlibrative nucleoside transporter (hENT1) inhibitors displaying K(i) values ranging from 10,000 to 0.7nM. Both CoMFA and CoMSIA analysis gave reliable models with q2 values >0.50 and r2 values >0.92. The models have been validated for their stability and robustness using group validation and bootstrapping techniques and for their predictive abilities using an external test set of nine compounds. The high predictive r2 values of the test set (0.72 for CoMFA model and 0.74 for CoMSIA model) reveals that the models can prove to be a useful tool for activity prediction of newly designed nucleoside transporter inhibitors. The CoMFA and CoMSIA contour maps identify features important for exhibiting good binding affinities at the transporter, and can thus serve as a useful guide for the design of potential equilibrative nucleoside transporter inhibitors.

DAT/SERT Selectivity of Flexible GBR 12909 Analogs Modeled Using 3D-QSAR Methods

PubMed Central

Gilbert, Kathleen M.; Boos, Terrence L.; Dersch, Christina M.; Greiner, Elisabeth; Jacobson, Arthur E.; Lewis, David; Matecka, Dorota; Prisinzano, Thomas E.; Zhang, Ying; Rothman, Richard B.; Rice, Kenner C.; Venanzi, Carol A.

2007-01-01

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pKi (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q2 = 0.508, standard error of prediction = 0.601, two components, r2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pKi (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. PMID:17127069

3D-QSAR and docking studies on 1-hydroxypyridin-2-one compounds as mutant isocitrate dehydrogenase 1 inhibitors

NASA Astrophysics Data System (ADS)

Wang, Zhenya; Chang, Yiqun; Han, Yushui; Liu, Kangjia; Hou, Jinsong; Dai, Chengli; Zhai, Yuanhao; Guo, Jialiang; Sun, Pinghua; Lin, Jing; Chen, Weimin

2016-11-01

Mutation of isocitrate dehydrogenase 1 (IDH1) which is frequently found in certain cancers such as glioma, sarcoma and acute myeloid leukemia, has been proven to be a potent drug target for cancer therapy. In silico methodologies such as 3D-QSAR and molecular docking were performed to explore compounds with better mutant isocitrate dehydrogenase 1 (MIDH1) inhibitory activity using a series of 40 newly reported 1-hydroxypyridin-2-one compounds as MIDH1 inhibitors. The satisfactory CoMFA and CoMSIA models obtained after internal and external cross-validation gave q2 values of 0.691 and 0.535, r2 values of 0.984 and 0.936, respectively. 3D contour maps generated from CoMFA and CoMSIA along with the docking results provided information about the structural requirements for better MIDH1 inhibitory activity. Based on the structure-activity relationship, 17 new potent molecules with better predicted activity than the most active compound in the literature have been designed.

Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking

NASA Astrophysics Data System (ADS)

Xie, Aihua; Odde, Srinivas; Prasanna, Sivaprakasam; Doerksen, Robert J.

2009-07-01

One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r 2 = 0.878, q 2 = 0.630, and r pred 2 = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents.

PubMed

Vyas, V K; Bhatt, H G; Patel, P K; Jalu, J; Chintha, C; Gupta, N; Ghate, M

2013-01-01

SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q²) of 0.602 and 0.618, respectively, and conventional coefficients (r²) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r² pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.

3D-QSAR studies and molecular docking on [5-(4-amino-1 H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors

NASA Astrophysics Data System (ADS)

Lan, Ping; Xie, Mei-Qi; Yao, Yue-Mei; Chen, Wan-Na; Chen, Wei-Min

2010-12-01

Fructose-1,6-biphophatase has been regarded as a novel therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). 3D-QSAR and docking studies were performed on a series of [5-(4-amino-1 H-benzoimidazol-2-yl)-furan-2-yl]-phosphonic acid derivatives as fructose-1,6-biphophatase inhibitors. The CoMFA and CoMSIA models using thirty-seven molecules in the training set gave r cv 2 values of 0.614 and 0.598, r 2 values of 0.950 and 0.928, respectively. The external validation indicated that our CoMFA and CoMSIA models possessed high predictive powers with r 0 2 values of 0.994 and 0.994, r m 2 values of 0.751 and 0.690, respectively. Molecular docking studies revealed that a phosphonic group was essential for binding to the receptor, and some key features were also identified. A set of forty new analogues were designed by utilizing the results revealed in the present study, and were predicted with significantly improved potencies in the developed models. The findings can be quite useful to aid the designing of new fructose-1,6-biphophatase inhibitors with improved biological response.

Towards discovering dual functional inhibitors against both wild type and K103N mutant HIV-1 reverse transcriptases: molecular docking and QSAR studies on 4,1-benzoxazepinone analogues

NASA Astrophysics Data System (ADS)

Zhang, Zhenshan; Zheng, Mingyue; Du, Li; Shen, Jianhua; Luo, Xiaomin; Zhu, Weiliang; Jiang, Hualiang

2006-05-01

To find useful information for discovering dual functional inhibitors against both wild type (WT) and K103N mutant reverse transcriptases (RTs) of HIV-1, molecular docking and 3D-QSAR approaches were applied to a set of twenty-five 4,1-benzoxazepinone analogues of efavirenz (SUSTIVA®), some of them are active against the two RTs. 3D-QSAR models were constructed, based on their binding conformations determined by molecular docking, with r 2 cv values ranging from 0.656 to 0.834 for CoMFA and CoMSIA, respectively. The models were then validated to be highly predictive and extrapolative by inhibitors in two test sets with different molecular skeletons. Furthermore, CoMFA models were found to be well matched with the binding sites of both WT and K103N RTs. Finally, a reasonable pharmacophore model of 4,1-benzoxazepinones were established. The application of the model not only successfully differentiated the experimentally determined inhibitors from non-inhibitors, but also discovered two potent inhibitors from the compound database SPECS. On the basis of both the 3D-QSAR and pharmacophore models, new clues for discovering and designing potent dual functional drug leads against HIV-1 were proposed: (i) adopting positively charged aliphatic group at the cis-substituent of C3; (ii) reducing the electronic density at the position of O4; (iii) positioning a small branched aliphatic group at position of C5; (iv) using the negatively charged bulky substituents at position of C7.

3D-QSAR pharmacophore-based virtual screening, molecular docking and molecular dynamics simulation toward identifying lead compounds for NS2B-NS3 protease inhibitors.

PubMed

Luo, Pei H; Zhang, Xuan R; Huang, Lan; Yuan, Lun; Zhou, Xang Z; Gao, X; Li, Ling S

2017-10-01

NS2B-NS3 protease has been identified to serve as lead drug design target due to its significant role in West Nile viral (WNV) and dengue virus (DENV) reproduction and replication. There are currently no approved chemotherapeutic drugs and effective vaccines to inhibit DENV and WNV infections. In this work, 3D-QSAR pharmacophore model has been developed to discover potential inhibitory candidates. Validation through Fischer's model and decoy test indicate that the developed 3D pharmacophore model is highly predictive for DENV inhibitors, which was then employed to screen ZINC chemical library to obtain reasonable hits. Following ADMET filtering, 15 hits were subjected to further filter through molecular docking and CoMFA modeling. Finally, top three hits were identified as lead compounds or potential inhibitory candidates with IC 50 values of ∼0.4637 µM and fitness of ∼57.73. It is implied from CoMFA modeling that substituents at the side site of benzotriazole such as a p-nitro group (e.g. biphenyl head) and a carbonyl (e.g. carboxylate function) at the side site of furan or amino group may improve bioactivity of ZINC85645245, respectively. Molecular dynamics simulations (MDS) were performed to discover new interactions and reinforce the binding modes from docking for the hits also. The QSAR and MDS results obtained from this work should be useful in determining structural requirements for inhibitor development as well as in designing more potential inhibitors for NS2B-NS3 protease.

A combined pharmacophore modeling, 3D-QSAR and molecular docking study of substituted bicyclo-[3.3.0]oct-2-enes as liver receptor homolog-1 (LRH-1) agonists

NASA Astrophysics Data System (ADS)

Lalit, Manisha; Gangwal, Rahul P.; Dhoke, Gaurao V.; Damre, Mangesh V.; Khandelwal, Kanchan; Sangamwar, Abhay T.

2013-10-01

A combined pharmacophore modelling, 3D-QSAR and molecular docking approach was employed to reveal structural and chemical features essential for the development of small molecules as LRH-1 agonists. The best HypoGen pharmacophore hypothesis (Hypo1) consists of one hydrogen-bond donor (HBD), two general hydrophobic (H), one hydrophobic aromatic (HYAr) and one hydrophobic aliphatic (HYA) feature. It has exhibited high correlation coefficient of 0.927, cost difference of 85.178 bit and low RMS value of 1.411. This pharmacophore hypothesis was cross-validated using test set, decoy set and Cat-Scramble methodology. Subsequently, validated pharmacophore hypothesis was used in the screening of small chemical databases. Further, 3D-QSAR models were developed based on the alignment obtained using substructure alignment. The best CoMFA and CoMSIA model has exhibited excellent rncv2 values of 0.991 and 0.987, and rcv2 values of 0.767 and 0.703, respectively. CoMFA predicted rpred2 of 0.87 and CoMSIA predicted rpred2 of 0.78 showed that the predicted values were in good agreement with the experimental values. Molecular docking analysis reveals that π-π interaction with His390 and hydrogen bond interaction with His390/Arg393 is essential for LRH-1 agonistic activity. The results from pharmacophore modelling, 3D-QSAR and molecular docking are complementary to each other and could serve as a powerful tool for the discovery of potent small molecules as LRH-1 agonists.

Design and preliminary structure-activity relationship of redox-silent semisynthetic tocotrienol analogues as inhibitors for breast cancer proliferation and invasion.

PubMed

Elnagar, Ahmed Y; Wali, Vikram B; Sylvester, Paul W; El Sayed, Khalid A

2010-01-15

Vitamin E (VE) is a generic term that represents a family of compounds composed of various tocopherol and tocotrienol isoforms. Tocotrienols display potent anti-angiogenic and antiproliferative activities. Redox-silent tocotrienol analogues also display potent anticancer activity. The ultimate objective of this study was to develop semisynthetically C-6-modified redox-silent tocotrienol analogues with enhanced antiproliferative and anti-invasive activities as compared to their parent compound. Examples of these are carbamate and ether analogues of alpha-, gamma-, and delta-tocotrienols (1-3). Various aliphatic, olefinic, and aromatic substituents were used. Steric limitation, electrostatic, hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) properties were varied at this position and the biological activities of these derivatives were tested. Three-dimensional quantitative structure-activity relationship (3D QSAR) studies were performed using Comparative Molecular Field (CoMFA) and Comparative Molecular Similarity Indices Analyses (CoMSIA) to better understand the structural basis for biological activity and guide the future design of more potent VE analogues. Copyright 2009 Elsevier Ltd. All rights reserved.

Development of quantitative structure-activity relationships and its application in rational drug design.

PubMed

Yang, Guang-Fu; Huang, Xiaoqin

2006-01-01

Over forty years have elapsed since Hansch and Fujita published their pioneering work of quantitative structure-activity relationships (QSAR). Following the introduction of Comparative Molecular Field Analysis (CoMFA) by Cramer in 1998, other three-dimensional QSAR methods have been developed. Currently, combination of classical QSAR and other computational techniques at three-dimensional level is of greatest interest and generally used in the process of modern drug discovery and design. During the last several decades, a number of different mythologies incorporating a range of molecular descriptors and different statistical regression ways have been proposed and successfully applied in developing of new drugs, thus QSAR method has been proven to be indispensable in not only the reliable prediction of specific properties of new compounds, but also the help to elucidate the possible molecular mechanism of the receptor-ligand interactions. Here, we review the recent developments in QSAR and their applications in rational drug design, focusing on the reasonable selection of novel molecular descriptors and the construction of predictive QSAR models by the help of advanced computational techniques.

In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

PubMed

Pagadala, Nataraj S; Perez-Pineiro, Rolando; Wishart, David S; Tuszynski, Jack A

2015-02-16

To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors

PubMed Central

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-01-01

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q2 = 0.621, r2pred = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained. PMID:26035757

A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors.

PubMed

Xie, Huiding; Chen, Lijun; Zhang, Jianqiang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

2015-05-29

B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained.

Profiling the interaction mechanism of quinoline/quinazoline derivatives as MCHR1 antagonists: an in silico method.

PubMed

Wu, Mingwei; Li, Yan; Fu, Xinmei; Wang, Jinghui; Zhang, Shuwei; Yang, Ling

2014-09-01

Melanin concentrating hormone receptor 1 (MCHR1), a crucial regulator of energy homeostasis involved in the control of feeding and energy metabolism, is a promising target for treatment of obesity. In the present work, the up-to-date largest set of 181 quinoline/quinazoline derivatives as MCHR1 antagonists was subjected to both ligand- and receptor-based three-dimensional quantitative structure-activity (3D-QSAR) analysis applying comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The optimal predictable CoMSIA model exhibited significant validity with the cross-validated correlation coefficient (Q²) = 0.509, non-cross-validated correlation coefficient (R²(ncv)) = 0.841 and the predicted correlation coefficient (R²(pred)) = 0.745. In addition, docking studies and molecular dynamics (MD) simulations were carried out for further elucidation of the binding modes of MCHR1 antagonists. MD simulations in both water and lipid bilayer systems were performed. We hope that the obtained models and information may help to provide an insight into the interaction mechanism of MCHR1 antagonists and facilitate the design and optimization of novel antagonists as anti-obesity agents.

QSAR, molecular docking studies of thiophene and imidazopyridine derivatives as polo-like kinase 1 inhibitors

NASA Astrophysics Data System (ADS)

Cao, Shandong

2012-08-01

The purpose of the present study was to develop in silico models allowing for a reliable prediction of polo-like kinase inhibitors based on a large diverse dataset of 136 compounds. As an effective method, quantitative structure activity relationship (QSAR) was applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The proposed QSAR models showed reasonable predictivity of thiophene analogs (Rcv2=0.533, Rpred2=0.845) and included four molecular descriptors, namely IC3, RDF075m, Mor02m and R4e+. The optimal model for imidazopyridine derivatives (Rcv2=0.776, Rpred2=0.876) was shown to perform good in prediction accuracy, using GATS2m and BEHe1 descriptors. Analysis of the contour maps helped to identify structural requirements for the inhibitors and served as a basis for the design of the next generation of the inhibitor analogues. Docking studies were also employed to position the inhibitors into the polo-like kinase active site to determine the most probable binding mode. These studies may help to understand the factors influencing the binding affinity of chemicals and to develop alternative methods for prescreening and designing of polo-like kinase inhibitors.

3D-QSAR based on quantum-chemical molecular fields: toward an improved description of halogen interactions.

PubMed

Güssregen, Stefan; Matter, Hans; Hessler, Gerhard; Müller, Marco; Schmidt, Friedemann; Clark, Timothy

2012-09-24

Current 3D-QSAR methods such as CoMFA or CoMSIA make use of classical force-field approaches for calculating molecular fields. Thus, they can not adequately account for noncovalent interactions involving halogen atoms like halogen bonds or halogen-π interactions. These deficiencies in the underlying force fields result from the lack of treatment of the anisotropy of the electron density distribution of those atoms, known as the "σ-hole", although recent developments have begun to take specific interactions such as halogen bonding into account. We have now replaced classical force field derived molecular fields by local properties such as the local ionization energy, local electron affinity, or local polarizability, calculated using quantum-mechanical (QM) techniques that do not suffer from the above limitation for 3D-QSAR. We first investigate the characteristics of QM-based local property fields to show that they are suitable for statistical analyses after suitable pretreatment. We then analyze these property fields with partial least-squares (PLS) regression to predict biological affinities of two data sets comprising factor Xa and GABA-A/benzodiazepine receptor ligands. While the resulting models perform equally well or even slightly better in terms of consistency and predictivity than the classical CoMFA fields, the most important aspect of these augmented field-types is that the chemical interpretation of resulting QM-based property field models reveals unique SAR trends driven by electrostatic and polarizability effects, which cannot be extracted directly from CoMFA electrostatic maps. Within the factor Xa set, the interaction of chlorine and bromine atoms with a tyrosine side chain in the protease S1 pocket are correctly predicted. Within the GABA-A/benzodiazepine ligand data set, PLS models of high predictivity resulted for our QM-based property fields, providing novel insights into key features of the SAR for two receptor subtypes and cross-receptor selectivity of the ligands. The detailed interpretation of regression models derived using improved QM-derived property fields thus provides a significant advantage by revealing chemically meaningful correlations with biological activity and helps in understanding novel structure-activity relationship features. This will allow such knowledge to be used to design novel molecules on the basis of interactions additional to steric and hydrogen-bonding features.

Molecular Determinants of Juvenile Hormone Action as Revealed by 3D QSAR Analysis in Drosophila

PubMed Central

Beňo, Milan; Farkaš, Robert

2009-01-01

Background Postembryonic development, including metamorphosis, of many animals is under control of hormones. In Drosophila and other insects these developmental transitions are regulated by the coordinate action of two principal hormones, the steroid ecdysone and the sesquiterpenoid juvenile hormone (JH). While the mode of ecdysone action is relatively well understood, the molecular mode of JH action remains elusive. Methodology/Principal Findings To gain more insights into the molecular mechanism of JH action, we have tested the biological activity of 86 structurally diverse JH agonists in Drosophila melanogaster. The results were evaluated using 3D QSAR analyses involving CoMFA and CoMSIA procedures. Using this approach we have generated both computer-aided and species-specific pharmacophore fingerprints of JH and its agonists, which revealed that the most active compounds must possess an electronegative atom (oxygen or nitrogen) at both ends of the molecule. When either of these electronegative atoms are replaced by carbon or the distance between them is shorter than 11.5 Å or longer than 13.5 Å, their biological activity is dramatically decreased. The presence of an electron-deficient moiety in the middle of the JH agonist is also essential for high activity. Conclusions/Significance The information from 3D QSAR provides guidelines and mechanistic scope for identification of steric and electrostatic properties as well as donor and acceptor hydrogen-bonding that are important features of the ligand-binding cavity of a JH target protein. In order to refine the pharmacophore analysis and evaluate the outcomes of the CoMFA and CoMSIA study we used pseudoreceptor modeling software PrGen to generate a putative binding site surrogate that is composed of eight amino acid residues corresponding to the defined molecular interactions. PMID:19547707

Structure-activity relationships of seco-prezizaane terpenoids in gamma-aminobutyric acid receptors of houseflies and rats.

PubMed

Kuriyama, Tadahiko; Schmidt, Thomas J; Okuyama, Emi; Ozoe, Yoshihisa

2002-06-01

Thirteen seco-prezizaane terpenoids isolated from star anise species (Illcium floridanum, Illcium parviflorum, and Illcium verum) were investigated for their ability to inhibit the specific binding of [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB), a non-competitive antagonist of gamma-aminobutyric acid (GABA) receptors, to housefly-head and rat-brain membranes. Veranisatin A was found to be the most potent inhibitor in both membranes, with an IC(50)(fly) of 78.5 nM and an IC(50)(rat) of 271 nM, followed by anisatin (IC(50)(fly)=123 nM; IC(50)(rat)=282 nM). Six of the other 11 tested compounds were effective only in housefly-head membranes. Pseudoanisatin proved to display a high (>26-fold) selectivity for housefly versus rat GABA receptors (IC(50)(fly)=376 nM; IC(50)(rat) >10,000 nM). Although pseudoanisatin does not structurally resemble EBOB, Scatchard plots indicated that the two compounds bind to the same site in housefly receptors. Anisatin and pseudoanisatin exhibited moderate insecticidal activity against German cockroaches. Comparative molecular field analysis (CoMFA), a method of three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis, demonstrated that seco-prezizaane terpenoids can bind to the same site as do picrotoxane terpenoids such as picrotoxinin and picrodendrins, and the CoMFA maps allowed us to identify the parts of the molecules essential to high activity in housefly GABA receptors.

General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors.

PubMed

Tsareva, Daria A; Osolodkin, Dmitry I; Shulga, Dmitry A; Oliferenko, Alexander A; Pisarev, Sergey A; Palyulin, Vladimir A; Zefirov, Nikolay S

2011-03-14

Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study. Here these charge models are used in CoMFA and CoMSIA methods and tested on five glycogen synthase kinase 3 (GSK-3) inhibitor datasets, relevant to our current studies, and one steroid dataset. For comparison, eight other different charge models, ab initio through semiempirical and empirical, were tested on the same datasets. The complex analysis including correlation and cross-validation, charges robustness and predictability, as well as visual interpretability of 3D contour maps generated was carried out. As a result, our new electronegativity relaxation-based models both have shown stable results, which in conjunction with other benefits discussed render them suitable for building reliable 3D QSAR models. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Molecular modeling-driven approach for identification of Janus kinase 1 inhibitors through 3D-QSAR, docking and molecular dynamics simulations.

PubMed

Itteboina, Ramesh; Ballu, Srilata; Sivan, Sree Kanth; Manga, Vijjulatha

2017-10-01

Janus kinase 1 (JAK 1) belongs to the JAK family of intracellular nonreceptor tyrosine kinase. JAK-signal transducer and activator of transcription (JAK-STAT) pathway mediate signaling by cytokines, which control survival, proliferation and differentiation of a variety of cells. Three-dimensional quantitative structure activity relationship (3 D-QSAR), molecular docking and molecular dynamics (MD) methods was carried out on a dataset of Janus kinase 1(JAK 1) inhibitors. Ligands were constructed and docked into the active site of protein using GLIDE 5.6. Best docked poses were selected after analysis for further 3 D-QSAR analysis using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methodology. Employing 60 molecules in the training set, 3 D-QSAR models were generate that showed good statistical reliability, which is clearly observed in terms of r 2 ncv and q 2 loo values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r 2 Pred ) values. The key amino acid residues were identified by means of molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good consonance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the reasonable modification of molecules in order to design more efficient JAK 1 inhibitors. The developed models are expected to provide some directives for further synthesis of highly effective JAK 1 inhibitors.

3D-QSAR, molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as mTOR inhibitor for the treatment of lung cancer.

PubMed

Chaube, Udit; Chhatbar, Dhara; Bhatt, Hardik

2016-02-01

According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer. Copyright © 2015 Elsevier Ltd. All rights reserved.

A 3D QSAR CoMFA study of non-peptide angiotensin II receptor antagonists

NASA Astrophysics Data System (ADS)

Belvisi, Laura; Bravi, Gianpaolo; Catalano, Giovanna; Mabilia, Massimo; Salimbeni, Aldo; Scolastico, Carlo

1996-12-01

A series of non-peptide angiotensin II receptor antagonists was investigated with the aim of developing a 3D QSAR model using comparative molecular field analysis descriptors and approaches. The main goals of the study were dictated by an interest in methodologies and an understanding of the binding requirements to the AT1 receptor. Consistency with the previously derived activity models was always checked to contemporarily test the validity of the various hypotheses. The specific conformations chosen for the study, the procedures invoked to superimpose all structures, the conditions employed to generate steric and electrostatic field values and the various PCA/PLS runs are discussed in detail. The effect of experimental design techniques to select objects (molecules) and variables (descriptors) with respect to the predictive power of the QSAR models derived was especially analysed.

Chemical Structure-Biological Activity Models for Pharmacophores’ 3D-Interactions

PubMed Central

Putz, Mihai V.; Duda-Seiman, Corina; Duda-Seiman, Daniel; Putz, Ana-Maria; Alexandrescu, Iulia; Mernea, Maria; Avram, Speranta

2016-01-01

Within medicinal chemistry nowadays, the so-called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/models by which given chemical structure or series of congeners actively act on biological sites either by focused interaction/therapy or by diffuse/hazardous influence. To this aim, the present review exposes three of the fertile directions in approaching the biological activity by chemical structural causes: the special computing trace of the algebraic structure-activity relationship (SPECTRAL-SAR) offering the full analytical counterpart for multi-variate computational regression, the minimal topological difference (MTD) as the revived precursor for comparative molecular field analyses (CoMFA) and comparative molecular similarity indices analysis (CoMSIA); all of these methods and algorithms were presented, discussed and exemplified on relevant chemical medicinal systems as proton pump inhibitors belonging to the 4-indolyl,2-guanidinothiazole class of derivatives blocking the acid secretion from parietal cells in the stomach, the 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine congeners’ (HEPT ligands) antiviral activity against Human Immunodeficiency Virus of first type (HIV-1) and new pharmacophores in treating severe genetic disorders (like depression and psychosis), respectively, all involving 3D pharmacophore interactions. PMID:27399692

Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor.

PubMed

Jozwiak, Krzysztof; Khalid, Chakir; Tanga, Mary J; Berzetei-Gurske, Ilona; Jimenez, Lucita; Kozocas, Joseph A; Woo, Anthony; Zhu, Weizhong; Xiao, Rui-Ping; Abernethy, Darrell R; Wainer, Irving W

2007-06-14

Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta2 adrenergic receptor (Kibeta2-AR), the subtype selectivity relative to the beta1-AR (Kibeta1-AR/Kibeta2-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The Kibeta1-AR/Kibeta2-AR ratios were >40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected Kibeta2 and subtype selectivity.

Insight into the interaction mechanism of human SGLT2 with its inhibitors: 3D-QSAR studies, homology modeling, and molecular docking and molecular dynamics simulations.

PubMed

Dong, Lili; Feng, Ruirui; Bi, Jiawei; Shen, Shengqiang; Lu, Huizhe; Zhang, Jianjun

2018-03-06

Human sodium-dependent glucose co-transporter 2 (hSGLT2) is a crucial therapeutic target in the treatment of type 2 diabetes. In this study, both comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to generate three-dimensional quantitative structure-activity relationship (3D-QSAR) models. In the most accurate CoMFA-based and CoMSIA-based QSAR models, the cross-validated coefficients (r 2 cv ) were 0.646 and 0.577, respectively, while the non-cross-validated coefficients (r 2 ) were 0.997 and 0.991, respectively, indicating that both models were reliable. In addition, we constructed a homology model of hSGLT2 in the absence of a crystal structure. Molecular docking was performed to explore the bonding mode of inhibitors to the active site of hSGLT2. Molecular dynamics (MD) simulations and binding free energy calculations using MM-PBSA and MM-GBSA were carried out to further elucidate the interaction mechanism. With regards to binding affinity, we found that hydrogen-bond interactions of Asn51 and Glu75, located in the active site of hSGLT2, with compound 40 were critical. Hydrophobic and electrostatic interactions were shown to enhance activity, in agreement with the results obtained from docking and 3D-QSAR analysis. Our study results shed light on the interaction mode between inhibitors and hSGLT2 and may aid in the development of C-aryl glucoside SGLT2 inhibitors.

DFT and 3D-QSAR Studies of Anti-Cancer Agents m-(4-Morpholinoquinazolin-2-yl) Benzamide Derivatives for Novel Compounds Design

NASA Astrophysics Data System (ADS)

Zhao, Siqi; Zhang, Guanglong; Xia, Shuwei; Yu, Liangmin

2018-06-01

As a group of diversified frameworks, quinazolin derivatives displayed a broad field of biological functions, especially as anticancer. To investigate the quantitative structure-activity relationship, 3D-QSAR models were generated with 24 quinazolin scaffold molecules. The experimental and predicted pIC50 values for both training and test set compounds showed good correlation, which proved the robustness and reliability of the generated QSAR models. The most effective CoMFA and CoMSIA were obtained with correlation coefficient r 2 ncv of 1.00 (both) and leave-one-out coefficient q 2 of 0.61 and 0.59, respectively. The predictive abilities of CoMFA and CoMSIA were quite good with the predictive correlation coefficients ( r 2 pred ) of 0.97 and 0.91. In addition, the statistic results of CoMFA and CoMSIA were used to design new quinazolin molecules.

Application of 3D-QSAR, Pharmacophore, and Molecular Docking in the Molecular Design of Diarylpyrimidine Derivatives as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors.

PubMed

Liu, Genyan; Wang, Wenjie; Wan, Youlan; Ju, Xiulian; Gu, Shuangxi

2018-05-11

Diarylpyrimidines (DAPYs), acting as HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs), have been considered to be one of the most potent drug families in the fight against acquired immunodeficiency syndrome (AIDS). To better understand the structural requirements of HIV-1 NNRTIs, three-dimensional quantitative structure⁻activity relationship (3D-QSAR), pharmacophore, and molecular docking studies were performed on 52 DAPY analogues that were synthesized in our previous studies. The internal and external validation parameters indicated that the generated 3D-QSAR models, including comparative molecular field analysis (CoMFA, q 2 = 0.679, R 2 = 0.983, and r pred 2 = 0.884) and comparative molecular similarity indices analysis (CoMSIA, q 2 = 0.734, R 2 = 0.985, and r pred 2 = 0.891), exhibited good predictive abilities and significant statistical reliability. The docking results demonstrated that the phenyl ring at the C₄-position of the pyrimidine ring was better than the cycloalkanes for the activity, as the phenyl group was able to participate in π⁻π stacking interactions with the aromatic residues of the binding site, whereas the cycloalkanes were not. The pharmacophore model and 3D-QSAR contour maps provided significant insights into the key structural features of DAPYs that were responsible for the activity. On the basis of the obtained information, a series of novel DAPY analogues of HIV-1 NNRTIs with potentially higher predicted activity was designed. This work might provide useful information for guiding the rational design of potential HIV-1 NNRTI DAPYs.

Structure-activity relationships of the antimalarial agent artemisinin. 8. design, synthesis, and CoMFA studies toward the development of artemisinin-based drugs against leishmaniasis and malaria.

PubMed

Avery, Mitchell A; Muraleedharan, Kannoth M; Desai, Prashant V; Bandyopadhyaya, Achintya K; Furtado, Marise M; Tekwani, Babu L

2003-09-25

Artemisinin (1) and its analogues have been well studied for their antimalarial activity. Here we present the antimalarial activity of some novel C-9-modified artemisinin analogues synthesized using artemisitene as the key intermediate. Further, antileishmanial activity of more than 70 artemisinin derivatives against Leishmania donovani promastigotes is described for the first time. A comprehensive structure-activity relationship study using CoMFA is discussed. These analogues exhibited leishmanicidal activity in micromolar concentrations, and the overall activity profile appears to be similar to that against malaria. Substitution at the C-9beta position was shown to improve the activity in both cases. The 10-deoxo derivatives showed better activity compared to the corresponding lactones. In general, compounds with C-9alpha substitution exhibited lower antimalarial as well as antileishmanial activities compared to the corresponding C-9beta analogues. The importance of the peroxide group for the observed activity of these analogues against leishmania was evident from the fact that 1-deoxyartemisinin analogues did not exhibit antileishmanial activity. The study suggests the possibility of developing artemisinin analogues as potential drug candidates against both malaria and leishmaniasis.

Discovery of unsymmetrical aromatic disulfides as novel inhibitors of SARS-CoV main protease: Chemical synthesis, biological evaluation, molecular docking and 3D-QSAR study.

PubMed

Wang, Li; Bao, Bo-Bo; Song, Guo-Qing; Chen, Cheng; Zhang, Xu-Meng; Lu, Wei; Wang, Zefang; Cai, Yan; Li, Shuang; Fu, Sheng; Song, Fu-Hang; Yang, Haitao; Wang, Jian-Guo

2017-09-08

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M pro ) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M pro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M pro . These novel compounds displayed excellent IC 50 data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Quantitative structure-property relationship modeling of Grätzel solar cell dyes.

PubMed

Venkatraman, Vishwesh; Åstrand, Per-Olof; Alsberg, Bjørn Kåre

2014-01-30

With fossil fuel reserves on the decline, there is increasing focus on the design and development of low-cost organic photovoltaic devices, in particular, dye-sensitized solar cells (DSSCs). The power conversion efficiency (PCE) of a DSSC is heavily influenced by the chemical structure of the dye. However, as far as we know, no predictive quantitative structure-property relationship models for DSSCs with PCE as one of the response variables have been reported. Thus, we report for the first time the successful application of comparative molecular field analysis (CoMFA) and vibrational frequency-based eigenvalue (EVA) descriptors to model molecular structure-photovoltaic performance relationships for a set of 40 coumarin derivatives. The results show that the models obtained provide statistically robust predictions of important photovoltaic parameters such as PCE, the open-circuit voltage (V(OC)), short-circuit current (J(SC)) and the peak absorption wavelength λ(max). Some of our findings based on the analysis of the models are in accordance with those reported in the literature. These structure-property relationships can be applied to the rational structural design and evaluation of new photovoltaic materials. Copyright © 2013 Wiley Periodicals, Inc.

Investigations of FAK inhibitors: a combination of 3D-QSAR, docking, and molecular dynamics simulations studies.

PubMed

Cheng, Peng; Li, Jiaojiao; Wang, Juan; Zhang, Xiaoyun; Zhai, Honglin

2018-05-01

Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in cancer cell migration, proliferation, and survival. To investigate the mechanism between FAK and triazinic inhibitors and design high activity inhibitors, a molecular modeling integrated with 3D-QSAR, molecular docking, molecular dynamics simulations, and binding free energy calculations was performed. The optimum CoMFA and CoMSIA models showed good reliability and satisfactory predictability (with Q 2  = 0.663, R 2  = 0.987, [Formula: see text] = 0.921 and Q 2  = 0.670, R 2  = 0.981, [Formula: see text] = 0.953). Its contour maps could provide structural features to improve inhibitory activity. Furthermore, a good consistency between contour maps, docking, and molecular dynamics simulations strongly demonstrates that the molecular modeling is reliable. Based on it, we designed several new compounds and their inhibitory activities were validated by the molecular models. We expect our studies could bring new ideas to promote the development of novel inhibitors with higher inhibitory activity for FAK.

Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors.

PubMed

Yu, Haijing; Fang, Yu; Lu, Xia; Liu, Yongjuan; Zhang, Huabei

2014-01-01

The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors. © 2013 John Wiley & Sons A/S.

Structure-based CoMFA as a predictive model - CYP2C9 inhibitors as a test case.

PubMed

Yasuo, Kazuya; Yamaotsu, Noriyuki; Gouda, Hiroaki; Tsujishita, Hideki; Hirono, Shuichi

2009-04-01

In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifications of the correct poses of each ligand by consensus scoring and MM-PBSA analysis, and a construction of a CoMFA model with the obtained poses to predict the affinity of the ligands. By using a crystal structure of CYP 2C9 and the twenty known CYP inhibitors as a test case, we obtained a CoMFA model with a good statistics, which suggested that the classification of the binding sites as well as the predicted bound poses of the ligands should be reasonable enough. The scheme described here would give a method to predict the affinity of small compounds with a reasonable accuracy, which is expected to heighten the value of computational chemistry in the drug design process.

Template CoMFA Generates Single 3D-QSAR Models that, for Twelve of Twelve Biological Targets, Predict All ChEMBL-Tabulated Affinities

PubMed Central

Cramer, Richard D.

2015-01-01

The possible applicability of the new template CoMFA methodology to the prediction of unknown biological affinities was explored. For twelve selected targets, all ChEMBL binding affinities were used as training and/or prediction sets, making these 3D-QSAR models the most structurally diverse and among the largest ever. For six of the targets, X-ray crystallographic structures provided the aligned templates required as input (BACE, cdk1, chk2, carbonic anhydrase-II, factor Xa, PTP1B). For all targets including the other six (hERG, cyp3A4 binding, endocrine receptor, COX2, D2, and GABAa), six modeling protocols applied to only three familiar ligands provided six alternate sets of aligned templates. The statistical qualities of the six or seven models thus resulting for each individual target were remarkably similar. Also, perhaps unexpectedly, the standard deviations of the errors of cross-validation predictions accompanying model derivations were indistinguishable from the standard deviations of the errors of truly prospective predictions. These standard deviations of prediction ranged from 0.70 to 1.14 log units and averaged 0.89 (8x in concentration units) over the twelve targets, representing an average reduction of almost 50% in uncertainty, compared to the null hypothesis of “predicting” an unknown affinity to be the average of known affinities. These errors of prediction are similar to those from Tanimoto coefficients of fragment occurrence frequencies, the predominant approach to side effect prediction, which template CoMFA can augment by identifying additional active structural classes, by improving Tanimoto-only predictions, by yielding quantitative predictions of potency, and by providing interpretable guidance for avoiding or enhancing any specific target response. PMID:26065424

New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: design, synthesis, biological assay, and 3D-QSAR analysis.

PubMed

Liu, Hong; Ji, Ming; Luo, Xiaomin; Shen, Jianhua; Huang, Xiaoqin; Hua, Weiyi; Jiang, Hualiang; Chen, Kaixian

2002-07-04

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrane action potential duration (APD). Using dofetilide (2) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a-d and 5a-l). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound 4a is 1.6 x 10(-8) mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 x 10(-8) mol/L. Compound 4a also produced a slightly lower change in ERP at 10(-5) M, DeltaERP% = 17.5% (DeltaERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e-h and 5m-s) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r(2) = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a-h) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10(-5) M compound 6c is much higher than that of dofetilide; the effective concentration of compound 6c is 5.0 x 10(-8)mol/L in increasing the ERP by 10 ms, which is slightly lower than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.

3D-QSAR and docking studies on 4-anilinoquinazoline and 4-anilinoquinoline epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

NASA Astrophysics Data System (ADS)

Assefa, Haregewein; Kamath, Shantaram; Buolamwini, John K.

2003-08-01

The overexpression and/or mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase has been observed in many human solid tumors, and is under intense investigation as a novel anticancer molecular target. Comparative 3D-QSAR analyses using different alignments were undertaken employing comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) for 122 anilinoquinazoline and 50 anilinoquinoline inhibitors of EGFR kinase. The SYBYL multifit alignment rule was applied to three different conformational templates, two obtained from a MacroModel Monte Carlo conformational search, and one from the bound conformation of erlotinib in complex with EGFR in the X-ray crystal structure. In addition, a flexible ligand docking alignment obtained with the GOLD docking program, and a novel flexible receptor-guided consensus dynamics alignment obtained with the DISCOVER program in the INSIGHTII modeling package were also investigated. 3D-QSAR models with q2 values up to 0.70 and r2 values up to 0.97 were obtained. Among the 4-anilinoquinazoline set, the q2 values were similar, but the ability of the different conformational models to predict the activities of an external test set varied considerably. In this regard, the model derived using the X-ray crystallographically determined bioactive conformation of erlotinib afforded the best predictive model. Electrostatic, hydrophobic and H-bond donor descriptors contributed the most to the QSAR models of the 4-anilinoquinazolines, whereas electrostatic, hydrophobic and H-bond acceptor descriptors contributed the most to the 4-anilinoquinoline QSAR, particularly the H-bond acceptor descriptor. A novel receptor-guided consensus dynamics alignment has also been introduced for 3D-QSAR studies. This new alignment method may incorporate to some extent ligand-receptor induced fit effects into 3D-QSAR models.

Quantitative insight into the design of compounds recognized by the L-type amino acid transporter 1 (LAT1).

PubMed

Ylikangas, Henna; Malmioja, Kalle; Peura, Lauri; Gynther, Mikko; Nwachukwu, Emmanuel O; Leppänen, Jukka; Laine, Krista; Rautio, Jarkko; Lahtela-Kakkonen, Maija; Huttunen, Kristiina M; Poso, Antti

2014-12-01

L-Type amino acid transporter 1 (LAT1) is a transmembrane protein expressed abundantly at the blood-brain barrier (BBB), where it ensures the transport of hydrophobic acids from the blood to the brain. Due to its unique substrate specificity and high expression at the BBB, LAT1 is an intriguing target for carrier-mediated transport of drugs into the brain. In this study, a comparative molecular field analysis (CoMFA) model with considerable statistical quality (Q(2) =0.53, R(2) =0.75, Q(2) SE=0.77, R(2) SE=0.57) and good external predictivity (CCC=0.91) was generated. The model was used to guide the synthesis of eight new prodrugs whose affinity for LAT1 was tested by using an in situ rat brain perfusion technique. This resulted in the creation of a novel LAT1 prodrug with L-tryptophan as the promoiety; it also provided a better understanding of the molecular features of LAT1-targeted high-affinity prodrugs, as well as their promoiety and parent drug. The results obtained will be beneficial in the rational design of novel LAT1-binding prodrugs and other compounds that bind to LAT1. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Studies of tricyclic piperazine/piperidine furnished molecules as novel integrin αvβ3/αIIbβ3 dual antagonists using 3D-QSAR and molecular docking.

PubMed

Yan, Yulian; Li, Yan; Zhang, Shuwei; Ai, Chunzhi

2011-02-01

The development of injectable integrin α(v)β(3)/α(IIb)β(3) dual antagonists attracts much attention of research for treating of acute ischemic diseases in recent years. In this work, based on a dataset composed of 102 tricyclic piperazine/piperidine furnished dual α(v)β(3) and α(IIb)β(3) antagonists, a variety of in silico modeling approaches including the comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), and molecular docking were applied to reveal the requisite 3D structural features impacting the biological activities. Our statistical results show that the ligand-based 3D-QSAR models for both the α(v)β(3) and α(IIb)β(3) studies exhibited satisfactory internal and external predictability, i.e., for the CoMFA models, results of Q(2)=0.48, R(ncv)(2)=0.87, R(pred)(2)=0.71 for α(v)β(3) and Q(2)=0.50, R(ncv)(2)=0.85, R(pred)(2)=0.72 for α(IIb)β(3) analysis were obtained, and for the CoMSIA ones, the outcomes of Q(2)=0.55, R(ncv)(2)=0.90, R(pred)(2)=0.72 for α(v)β(3) and Q(2)=0.52, R(ncv)(2)=0.88, R(pred)(2)=0.74 for α(IIb)β(3) were achieved respectively. In addition, through a comparison between 3D-QSAR contour maps and docking results, it is revealed that that the most crucial interactions occurring between the tricyclic piperazine/piperidine derivatives and α(v)β(3)/α(IIb)β(3) receptor ligand binding pocket are H-bonding, and the key amino acids impacting the interactions are Arg214, Asn215, Ser123, and Lys253 for α(v)β(3), but Arg214, Asn215, Ser123 and Tyr190 for α(IIb)β(3) receptors, respectively. Halogen-containing groups at position 15 and 16, benzene sulfonamide substituent at position 23, and the replacement of piperazine with 4-aminopiperidine of ring B may increase the α(v)β(3)/α(IIb)β(3) antagonistic activity. The potencies for antagonists to inhibit isolated α(v)β(3) and α(IIb)β(3) are linear correlated, indicating that similar interaction mechanisms may exist for the series of molecules. To our best knowledge this is the first report on 3D-QSAR modeling of these dual α(v)β(3)/α(IIb)β(3) antagonists. The results obtained should provide information for better understanding of the mechanism of antagonism and thus be helpful in design of novel potent dual α(v)β(3)/α(IIb)β(3) antagonists. Copyright © 2011 Elsevier Inc. All rights reserved.

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations.

PubMed

Qian, Haiyan; Chen, Jiongjiong; Pan, Youlu; Chen, Jianzhong

2016-09-19

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.

Thermal comfort modelling of body temperature and psychological variations of a human exercising in an outdoor environment

NASA Astrophysics Data System (ADS)

Vanos, Jennifer K.; Warland, Jon S.; Gillespie, Terry J.; Kenny, Natasha A.

2012-01-01

Human thermal comfort assessments pertaining to exercise while in outdoor environments can improve urban and recreational planning. The current study applied a simple four-segment skin temperature approach to the COMFA (COMfort FormulA) outdoor energy balance model. Comparative results of measured mean skin temperature ( {{bar{T}}}nolimits_{{Msk}} ) with predicted {{bar{T}}}nolimits_{{sk}} indicate that the model accurately predicted {{bar{T}}}nolimits_{{sk}} , showing significantly strong agreement ( r = 0.859, P < 0.01) during outdoor exercise (cycling and running). The combined 5-min mean variation of the {{bar{T}}}nolimits_{{sk}} RMSE was 1.5°C, with separate cycling and running giving RMSE of 1.4°C and 1.6°C, respectively, and no significant difference in residuals. Subjects' actual thermal sensation (ATS) votes displayed significant strong rank correlation with budget scores calculated using both measured and predicted {{bar{T}}}nolimits_{{sk}} ( r s = 0.507 and 0.517, respectively, P < 0.01). These results show improved predictive strength of ATS of subjects as compared to the original and updated COMFA models. This psychological improvement, plus {{bar{T}}}nolimits_{{sk}} and T c validations, enables better application to a variety of outdoor spaces. This model can be used in future research studying linkages between thermal discomfort, subsequent decreases in physical activity, and negative health trends.

Structure-Activity Correlations for β-Phenethylamines at Human Trace Amine Receptor 1

PubMed Central

Lewin, Anita H.; Navarro, Hernán A.; Mascarella, S. Wayne

2008-01-01

A cell line in which RD-HGA16 cells were stably transfected with the hTAAR 1 receptor was created and utilized to carry out a systematic evaluation of a series of β-phenethylamines. Fair agreement was observed with data obtained for aryl and ethylene chain substituted analogs in an AV12-664 cell line in which hemagglutinin-tagged hTAAR 1 was stably co-expressed with rat Gαs. Analogs with multiple substituents as well as analogs with bulky groups were found to be partial agonists. Analogs in which the primary amino group was converted to a secondary or a tertiary amino group by N-methylation were also partial agonists. Comparative Molecular Field Analysis (CoMFA) using the potency data yielded a regression coefficient r2 of 0.824. The steric field contribution to the model was 61% with the balance (39%) contributed by the electrostatic field. The collective results suggest that increasing steric bulk at both the amino nitrogen, particularly by N-dimethylation, and at the 4-position of the aromatic ring, leads to low efficacy ligands. PMID:18602830

Designing the molecular future.

PubMed

Schneider, Gisbert

2012-01-01

Approximately 25 years ago the first computer applications were conceived for the purpose of automated 'de novo' drug design, prominent pioneering tools being ALADDIN, CAVEAT, GENOA, and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand-receptor interaction modeling like GRID, MCSS, DOCK, and CoMFA, which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking applications in the 1990s--expressly GROW, GrowMol, LEGEND, and LUDI representing some of the key players--we are currently witnessing a renewed strong interest in this field. Innovative ideas for both receptor and ligand-based drug design have recently been published. We here provide a personal perspective on the evolution of de novo design, highlighting some of the historic achievements as well as possible future developments of this exciting field of research, which combines multiple scientific disciplines and is, like few other areas in chemistry, subject to continuous enthusiastic discussion and compassionate dispute.

Designing the molecular future

NASA Astrophysics Data System (ADS)

Schneider, Gisbert

2012-01-01

Approximately 25 years ago the first computer applications were conceived for the purpose of automated `de novo' drug design, prominent pioneering tools being ALADDIN, CAVEAT, GENOA, and DYLOMMS. Many of these early concepts were enabled by innovative techniques for ligand-receptor interaction modeling like GRID, MCSS, DOCK, and CoMFA, which still provide the theoretical framework for several more recently developed molecular design algorithms. After a first wave of software tools and groundbreaking applications in the 1990s—expressly GROW, GrowMol, LEGEND, and LUDI representing some of the key players—we are currently witnessing a renewed strong interest in this field. Innovative ideas for both receptor and ligand-based drug design have recently been published. We here provide a personal perspective on the evolution of de novo design, highlighting some of the historic achievements as well as possible future developments of this exciting field of research, which combines multiple scientific disciplines and is, like few other areas in chemistry, subject to continuous enthusiastic discussion and compassionate dispute.

3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

PubMed Central

Zhang, Baidong; Li, Yan; Zhang, Huixiao; Ai, Chunzhi

2010-01-01

Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q2 = 0.605, r2pred = 0.826), (q2 = 0.52, r2pred = 0.798) and (q2 = 0.582, r2pred = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors. PMID:21151441

3D-QSAR and molecular docking studies on derivatives of MK-0457, GSK1070916 and SNS-314 as inhibitors against Aurora B kinase.

PubMed

Zhang, Baidong; Li, Yan; Zhang, Huixiao; Ai, Chunzhi

2010-11-02

Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(2) (pred) = 0.826), (q(2) = 0.52, r(2) (pred) = 0.798) and (q(2) = 0.582, r(2) (pred) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.

Synthesis, Antifungal Activity and Structure-Activity Relationships of Novel 3-(Difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic Acid Amides.

PubMed

Du, Shijie; Tian, Zaimin; Yang, Dongyan; Li, Xiuyun; Li, Hong; Jia, Changqing; Che, Chuanliang; Wang, Mian; Qin, Zhaohai

2015-05-08

A series of novel 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid amides were synthesized and their activities were tested against seven phytopathogenic fungi by an in vitro mycelia growth inhibition assay. Most of them displayed moderate to excellent activities. Among them N-(2-(5-bromo-1H-indazol-1-yl)phenyl)-3-(difluoro-methyl)-1-methyl-1H-pyrazole-4-carboxamide (9m) exhibited higher antifungal activity against the seven phytopathogenic fungi than boscalid. Topomer CoMFA was employed to develop a three-dimensional quantitative structure-activity relationship model for the compounds. In molecular docking, the carbonyl oxygen atom of 9m could form hydrogen bonds towards the hydroxyl of TYR58 and TRP173 on SDH.

3D-Quantitative structure-activity relationships of synthetic antileishmanial ring-substituted ether phospholipids.

PubMed

Kapou, Agnes; Benetis, Nikolas P; Avlonitis, Nikos; Calogeropoulou, Theodora; Koufaki, Maria; Scoulica, Efi; Nikolaropoulos, Sotiris S; Mavromoustakos, Thomas

2007-02-01

The application of 2D-NMR spectroscopy and Molecular Modeling in determining the active conformation of flexible molecules in 3D-QSAR was demonstrated in the present study. In particular, a series of 33 flexible synthetic phospholipids, either 2-(4-alkylidene-cyclohexyloxy)ethyl- or omega-cycloalkylidene-substituted ether phospholipids were systematically evaluated for their in vitro antileishmanial activity against the promastigote forms of Leishmania infantum and Leishmania donovani by CoMFA and CoMSIA 3D-QSAR studies. Steric and hydrophobic properties of the phospholipids under study appear to govern their antileishmanial activity against both strains, while the electrostatic properties have no significant contribution. The acknowledgment of these important properties of the pharmacophore will aid in the rational design of new analogues with higher activity.

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARγ

PubMed Central

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-01-01

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49∼94.1 nM against AT1 and EC50s of 20∼3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists. PMID:28445965

Molecular docking, 3D-QSAR and structural optimization on imidazo-pyridine derivatives dually targeting AT1 and PPARg.

PubMed

Zhang, Jun; Hao, Qing-Qing; Liu, Xin; Jing, Zhi; Jia, Wen-Qing; Wang, Shu-Qing; Xu, Wei-Ren; Cheng, Xian-Chao; Wang, Run-Ling

2017-04-11

Telmisartan, a bifunctional agent of blood pressure lowering and glycemia reduction, was previously reported to antagonize angiotensin II type 1 (AT1) receptor and partially activate peroxisome proliferator-activated receptor γ (PPARγ) simultaneously. Through the modification to telmisartan, researchers designed and obtained imidazo-\\pyridine derivatives with the IC50s of 0.49~94.1 nM against AT1 and EC50s of 20~3640 nM towards PPARγ partial activation. For minutely inquiring the interaction modes with the relevant receptor and analyzing the structure-activity relationships, molecular docking and 3D-QSAR (Quantitative structure-activity relationships) analysis of these imidazo-\\pyridines on dual targets were conducted in this work. Docking approaches of these derivatives with both receptors provided explicit interaction behaviors and excellent matching degree with the binding pockets. The best CoMFA (Comparative Molecular Field Analysis) models exhibited predictive results of q2=0.553, r2=0.954, SEE=0.127, r2pred=0.779 for AT1 and q2=0.503, r2=1.00, SEE=0.019, r2pred=0.604 for PPARγ, respectively. The contour maps from the optimal model showed detailed information of structural features (steric and electrostatic fields) towards the biological activity. Combining the bioisosterism with the valuable information from above studies, we designed six molecules with better predicted activities towards AT1 and PPARγ partial activation. Overall, these results could be useful for designing potential dual AT1 antagonists and partial PPARγ agonists.

Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

PubMed Central

Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

2013-01-01

The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

Improved predictive ability of climate-human-behaviour interactions with modifications to the COMFA outdoor energy budget model.

PubMed

Vanos, J K; Warland, J S; Gillespie, T J; Kenny, N A

2012-11-01

The purpose of this paper is to implement current and novel research techniques in human energy budget estimations to give more accurate and efficient application of models by a variety of users. Using the COMFA model, the conditioning level of an individual is incorporated into overall energy budget predictions, giving more realistic estimations of the metabolism experienced at various fitness levels. Through the use of VO(2) reserve estimates, errors are found when an elite athlete is modelled as an unconditioned or a conditioned individual, giving budgets underpredicted significantly by -173 and -123 W m(-2), respectively. Such underprediction can result in critical errors regarding heat stress, particularly in highly motivated individuals; thus this revision is critical for athletic individuals. A further improvement in the COMFA model involves improved adaptation of clothing insulation (I (cl)), as well clothing non-uniformity, with changing air temperature (T (a)) and metabolic activity (M (act)). Equivalent T (a) values (for I (cl) estimation) are calculated in order to lower the I (cl) value with increasing M (act) at equal T (a). Furthermore, threshold T (a) values are calculated to predict the point at which an individual will change from a uniform I (cl) to a segmented I (cl) (full ensemble to shorts and a T-shirt). Lastly, improved relative velocity (v (r)) estimates were found with a refined equation accounting for the degree angle of wind to body movement. Differences between the original and improved v (r) equations increased with higher wind and activity speeds, and as the wind to body angle moved away from 90°. Under moderate microclimate conditions, and wind from behind a person, the convective heat loss and skin temperature estimates were 47 W m(-2) and 1.7°C higher when using the improved v (r) equation. These model revisions improve the applicability and usability of the COMFA energy budget model for subjects performing physical activity in outdoor environments. Application is possible for other similar energy budget models, and within various urban and rural environments.

Improved predictive ability of climate-human-behaviour interactions with modifications to the COMFA outdoor energy budget model

NASA Astrophysics Data System (ADS)

Vanos, J. K.; Warland, J. S.; Gillespie, T. J.; Kenny, N. A.

2012-11-01

The purpose of this paper is to implement current and novel research techniques in human energy budget estimations to give more accurate and efficient application of models by a variety of users. Using the COMFA model, the conditioning level of an individual is incorporated into overall energy budget predictions, giving more realistic estimations of the metabolism experienced at various fitness levels. Through the use of VO2 reserve estimates, errors are found when an elite athlete is modelled as an unconditioned or a conditioned individual, giving budgets underpredicted significantly by -173 and -123 W m-2, respectively. Such underprediction can result in critical errors regarding heat stress, particularly in highly motivated individuals; thus this revision is critical for athletic individuals. A further improvement in the COMFA model involves improved adaptation of clothing insulation ( I cl), as well clothing non-uniformity, with changing air temperature ( T a) and metabolic activity ( M act). Equivalent T a values (for I cl estimation) are calculated in order to lower the I cl value with increasing M act at equal T a. Furthermore, threshold T a values are calculated to predict the point at which an individual will change from a uniform I cl to a segmented I cl (full ensemble to shorts and a T-shirt). Lastly, improved relative velocity ( v r) estimates were found with a refined equation accounting for the degree angle of wind to body movement. Differences between the original and improved v r equations increased with higher wind and activity speeds, and as the wind to body angle moved away from 90°. Under moderate microclimate conditions, and wind from behind a person, the convective heat loss and skin temperature estimates were 47 W m-2 and 1.7°C higher when using the improved v r equation. These model revisions improve the applicability and usability of the COMFA energy budget model for subjects performing physical activity in outdoor environments. Application is possible for other similar energy budget models, and within various urban and rural environments.

The discovery of novel histone lysine methyltransferase G9a inhibitors (part 1): molecular design based on a series of substituted 2,4-diamino-7- aminoalkoxyquinazoline by molecular-docking-guided 3D quantitative structure-activity relationship studies.

PubMed

Feng, Taotao; Wang, Hai; Zhang, Xiaojin; Sun, Haopeng; You, Qidong

2014-06-01

Protein lysine methyltransferase G9a, which catalyzes methylation of lysine 9 of histone H3 (H3K9) and lysine 373 (K373) of p53, is overexpressed in human cancers. This suggests that small molecular inhibitors of G9a might be attractive antitumor agents. Herein we report our efforts on the design of novel G9a inhibitor based on the 3D quantitative structure-activity relationship (3D-QSAR) analysis of a series of 2,4-diamino-7-aminoalkoxyquinazolineas G9a inhibitors. The 3D-QSAR model was generated from 47 compounds using docking based molecular alignment. The best predictions were obtained with CoMFA standard model (q2 =0.700, r2 = 0.952) and CoMSIA model combined with steric, electrostatic, hydrophobic, hydrogen bond donor and acceptor fields (q2 = 0.724, r2 =0.960). The structural requirements for substituted 2,4-diamino-7-aminoalkoxyquinazoline for G9a inhibitory activity can be obtained by analysing the COMSIA plots. Based on the information, six novel follow-up analogs were designed.

Computational Study Exploring the Interaction Mechanism of Benzimidazole Derivatives as Potent Cattle Bovine Viral Diarrhea Virus Inhibitors.

PubMed

Wang, Jinghui; Yang, Yinfeng; Li, Yan; Wang, Yonghua

2016-07-27

Bovine viral diarrhea virus (BVDV) infections are prevailing in cattle populations on a worldwide scale. The BVDV RNA-dependent RNA polymerase (RdRp), as a promising target for new anti-BVDV drug development, has attracted increasing attention. To explore the interaction mechanism of 65 benzimidazole scaffold-based derivatives as BVDV inhibitors, presently, a computational study was performed based on a combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) simulations. The resultant optimum CoMFA and CoMSIA models present proper reliabilities and strong predictive abilities (with Q(2) = 0. 64, R(2)ncv = 0.93, R(2)pred = 0.80 and Q(2) = 0. 65, R(2)ncv = 0.98, R(2)pred = 0.86, respectively). In addition, there was good concordance between these models, molecular docking, and MD results. Moreover, the MM-PBSA energy analysis reveals that the major driving force for ligand binding is the polar solvation contribution term. Hopefully, these models and the obtained findings could offer better understanding of the interaction mechanism of BVDV inhibitors as well as benefit the new discovery of more potent BVDV inhibitors.

Synthesis, fungicidal activity, structure-activity relationships (SARs) and density functional theory (DFT) studies of novel strobilurin analogues containing arylpyrazole rings.

PubMed

Liu, Yuanyuan; Lv, Kunzhi; Li, Yi; Nan, Qiuli; Xu, Jinyuan

2018-05-18

A series of novel strobilurin analogues (1a-1f, 2a-2e, 3a-3e) containing arylpyrazole rings were synthesized and characterized by NMR spectroscopy. The structures of 1f, 2b and 3b were also determined by single crystal X-ray diffraction analysis. These analogues were collected together with other twenty-eight similar compounds 4a-4f, 5a-5h, 6a-6h and 7a-7f from our previous studies, for in vitro bioassays and thorough structure-activity relationships (SARs) studies. Most compounds exhibited excellent-to-good fungicidal activity against Rhizoctonia solani, especially 5c, 7a, 6c, and 3b with 98.94%, 83.40%, 71.40% and 65.87% inhibition rates at 0.1 μg mL -1 , respectively, better than commercial pyraclostrobin. Comparative molecular field analysis (CoMFA) was employed to study three-dimensional quantitative structure-activity relationships (3D-QSARs). Density functional theory (DFT) calculation was also carried out to provide more information regarding SARs. The present work provided some hints for developing novel strobilurin fungicides.

Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: an in silico analysis.

PubMed

Li, Yan; Wu, Wenzhao; Ren, Hong; Wang, Jinghui; Zhang, Shuwei; Li, Guohui; Yang, Ling

2012-09-01

Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q² of 0.584, R(ncv)² of 0.884 and R(pre)² of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the π-π stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27-position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and π-π stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity. Copyright © 2012 Elsevier Inc. All rights reserved.

The structural requirements of organophosphorus insecticides (OPI) for reducing chicken embryo NAD(+) content in OPI-induced teratogenesis in chickens.

PubMed

Seifert, Josef

2016-05-01

The objective of this study was to determine the structural requirements of organophosphorus insecticides (OPI) for reducing chicken embryo nicotinamide adenine dinucleotide (NAD(+)) content in OPI-induced teratogenesis and compare them with those needed for OPI inhibition of yolk sac membrane kynurenine formamidase (KFase), the proposed primary target for OPI teratogens in chicken embryos. The comparative molecular field analysis (COMFA) of three-dimensional quantitative structure-activity relationship (3D QSAR) revealed the electrostatic and steric fields as good predictors of OPI structural requirements to reduce NAD(+) content in chicken embryos. The dominant electrostatic interactions were localized at nitrogen-1, nitrogen-3, nitrogen of 2-amino substituent of the pyrimidinyl of pyrimidinyl phosphorothioates, and at the oxygen of crotonamide carbonyl in crotonamide phosphates. Bulkiness of the substituents at carbon-6 of the pyrimidinyls and/or N-substituents of crotonamides was the steric structural component that contributed to superiority of those OPI for reducing embryonic NAD(+) levels. Both electrostatic and steric requirements are similar to those defined in our previous study for OPI inhibition of chicken embryo yolk sac membrane KFase. The findings of this study provide another piece of evidence for the cause-and-effect relationship between yolk sac membrane KFase inhibition and reduced embryo NAD(+) content in NAD-associated OPI-induced teratogenesis in chickens. Copyright © 2015 Elsevier Inc. All rights reserved.

Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors.

PubMed

Mao, Yating; Li, Yan; Hao, Ming; Zhang, Shuwei; Ai, Chunzhi

2012-05-01

As a key component in combination therapy for acquired immunodeficiency syndrome (AIDS), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been proven to be an essential way in stopping HIV-1 replication. In the present work, in silico studies were conducted on a series of 119 NNRTIs, including 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives by using the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking simulations and molecular dynamics (MD). The statistical results of the optimal model, the ligand-based CoMSIA one (Q(2) = 0.48, R(ncv)(2) =0.847, R(pre)(2) = 0.745) validates its satisfactory predictive capacity both internally and externally. The contour maps, docking and MD results correlate well with each other, drawing conclusions as follows: 1) Compounds with bulky substituents in position-6 of ring A, hydrophobic groups around position- 1, 2, 6 are preferable to the biological activities; 2) Two hydrogen bonds between RT inhibitor and the Tyr 318, Lys 101 residues, respectively, and a π-π bond between the inhibitor and Trp 188 are formed and crucial to the orientation of the active conformation of the molecules; 3) The binding pocket is essentially hydrophobic, which are determined by residues such as Trp 229, Tyr 318, Val 179, Tyr 188 and Val 108, and hydrophobic substituents may bring an improvement to the biological activity; 4) DABO and HEPT derivatives have different structures but take a similar mechanism to inhibit RT. The potency difference between two isomers in HEPTs can be explained by the distinct locations of the 6-naphthylmethyl substituent and the reasons are explained in details. All these results could be employed to alter the structural scaffold in order to develop new HIV-1 RT inhibitors that have an improved biological property. To the best of our knowledge, this is the first report on 3D-QSAR modeling of this series of HEPT and DABO NNRTs. The QSAR model and the information derived, we hope, will be of great help in presenting clear guidelines and accurate activity predictions for newly designed HIV-1 reverse transcriptase (RT) inhibitor.

Modification of polychlorinated phenols and evaluation of their toxicity, biodegradation and bioconcentration using three-dimensional quantitative structure-activity relationship models.

PubMed

Tong, Lidan; Guo, Lixin; Lv, Xiaojun; Li, Yu

2017-01-01

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were established by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Experimental toxicity data in Poecilia reticulata (pLC 50 ) and physico-chemical properties for 12 polychlorinated phenols were used as dependent and as independent variables, respectively. Among the 12 polychlorinated phenols, nine were randomly selected and used as a training set to construct the 3D-QSAR models through the SYBYL-X software to predict the pLC 50 values of the remaining 8 polychlorinated phenols congeners, and the other three polychlorinated phenols were used as a test set to evaluate the 3D-QSAR models (the training set and test set were arranged randomly, shuffled 60 times). Pentachlorophenol (PCP), which is the most toxic among the 20 polychlorinated phenols used in this experiment, was selected as an example for modification using contour maps produced using the established 3D-QSAR models. The aim was to decrease its toxicity and bioconcentration, increase its biodegradation, and maintain or better its effectiveness as a pesticide. The 3D-QSAR models were robust and had good predictive abilities with cross-validation correlation coefficients (q 2 ) of 0.858-0.992 (>0.5), correlation coefficients (r 2 ) of 0.966-1.000 (>0.9), and standard errors of prediction (SEP) of 0.004-0.159. CoMFA showed that the toxicity of the polychlorinated phenols arose mainly from electrostatic (42.7-66.7%) and steric (33.3-7.3%) contributions. By comparison, CoMSIA showed that the toxicity of polychlorinated phenols was dominated by electrostatic (57.5-76.9%) and hydrophobic (19.8-25.7%) contributions, with lesser contributions from the steric (0.7-1.0%) hydrogen bond donor (0.1-20.3%), and hydrogen bond acceptor (0-0.9%). 3D-QSAR electrostatic contour maps were used to modify PCP and design 11 new compounds with lower toxicity. The effectiveness of each of these molecules as a pesticide was verified using a 3D-QSAR model for polychlorinated phenol toxicity against Tetrahymena pyriformis. Four of these compounds, with -Br, -I, -OH and -NH 2 groups in place of chlorine at the 3-position on PCP, were all at least as effective as PCP against T. Pyriformis. The first-order rate constants (K b ) of these four compounds were predicted using a 3D-QSAR model for polychlorinated phenol degradation, which showed they were more biodegradable than PCP. Furthermore, a 3D-QSAR model for polychlorinated phenols bioconcentration in fish (containing Poecilia reticulata, Oncorhynchus mykiss, Pimephales promelas and Oryzias latipes) showed that there was no significant difference between the bioconcentration factors of the four new compounds and that of PCP. The results obtained are hoped to provide a new route for lowering the POPs characteristics of those polychlorinated phenol homologues and derivatives in use. Copyright © 2016 Elsevier Inc. All rights reserved.

A Drug Discovery Partnership for Personalized Breast Cancer Therapy

DTIC Science & Technology

2012-09-01

flexible searches of compound databases using detailed pharmacophore and CoMFA QSAR results. (Months 9-24). 1,3,8-trihydroxyanthraquinone was taken...Cytochrome P450 Inhibitors- A Study of Their Potency and Selectivity”, J. Sridhar, J. Liu, C.L.K. Stevens, and M. Foroozesh, Society of Toxicology

Derivation of a 3D pharmacophore model for the angiotensin-II site one receptor

NASA Astrophysics Data System (ADS)

Prendergast, Kristine; Adams, Kym; Greenlee, William J.; Nachbar, Robert B.; Patchett, Arthur A.; Underwood, Dennis J.

1994-10-01

A systematic search has been used to derive a hypothesis for the receptor-bound conformation of A-II antagonists at the AT1 receptor. The validity of the pharmacophore hypothesis has been tested using CoMFA, which included 50 diverse A-II antagonists, spanning four orders of magnitude in activity. The resulting cross-validated R2 of 0.64 (conventional R2 of 0.76) is indicative of a good predictive model of activity, and has been used to estimate potency for a variety of non-peptidyl antagonists. The structural model for the non-peptide has been compared with respect to the natural substrate, A-II, by generating peptide to non-peptide overlays.

Drug design for ever, from hype to hope

NASA Astrophysics Data System (ADS)

Seddon, G.; Lounnas, V.; McGuire, R.; van den Bergh, T.; Bywater, R. P.; Oliveira, L.; Vriend, G.

2012-01-01

In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

Synthesis and biological activities of turkesterone 11α-acyl derivatives

PubMed Central

Dinan, Laurence; Bourne, Pauline; Whiting, Pensri; Tsitsekli, Ada; Saatov, Ziyadilla; Dhadialla, Tarlochan S.; Hormann, Robert E.; Lafont, René; Coll, Josep

2003-01-01

Turkesterone is a phytoecdysteroid possessing an 11α-hydroxyl group. It is an analogue of the insect steroid hormone 20-hydroxyecdysone. Previous ecdysteroid QSAR and molecular modelling studies predicted that the cavity of the ligand binding domain of the ecdysteroid receptor would possess space in the vicinity of C-11/C-12 of the ecdysteroid. We report the regioselective synthesis of a series of turkesterone 11α-acyl derivatives in order to explore this possibility. The structures of the analogues have been unambiguously determined by spectroscopic means (NMR and low-resolution mass spectrometry). Purity was verified by HPLC. Biological activities have been determined in Drosophila melanogaster BII cell-based bioassay for ecdysteroid agonists and in an in vitro radioligand-displacement assay using bacterially-expressed D. melanogaster EcR/USP receptor proteins. The 11α-acyl derivatives do retain a significant amount of biological activity relative to the parent ecdysteroid. Further, although activity initially drops with the extension of the acyl chain length (C2 to C4), it then increases (C6 to C10), before decreasing again (C14 and C20). The implications of these findings for the interaction of ecdysteroids with the ecdysteroid receptor and potential applications in the generation of affinity-labelled and fluorescently-tagged ecdysteroids are discussed. Abbreviation: CoMFA comparative molecular field analysis DCM dichloromethane DMF dimethylformamide DMP 2,2-dimethoxypropane 4D-QSAR 4-dimensional quantitative structure-activity relationship EcR ecdysteroid receptor EcRE ecdysteroid response element HPLC high-performance liquid chromatography LBD ligand-binding domain NMR nuclear magnetic resonance ponA ponasterone A QSAR quantitative structure-activity relationship RXR retinoid X receptor SAR structure-activity relationship SPE solid-phase extraction THF tetrahydrofuran TLC thin-layer chromatography p-TsOH para-toluenesulphonic acid USP ultraspiracle UV-VIS ultraviolet-visible PMID:15841223

Comparative Analysis of Pharmacophore Features and Quantitative Structure-Activity Relationships for CD38 Covalent and Non-covalent Inhibitors.

PubMed

Zhang, Shuang; Xue, Xiwen; Zhang, Liangren; Zhang, Lihe; Liu, Zhenming

2015-12-01

In the past decade, the discovery, synthesis, and evaluation for hundreds of CD38 covalent and non-covalent inhibitors has been reported sequentially by our group and partners; however, a systematic structure-based guidance is still lacking for rational design of CD38 inhibitor. Here, we carried out a comparative analysis of pharmacophore features and quantitative structure-activity relationships for CD38 inhibitors. The results uncover that the essential interactions between key residues and covalent/non-covalent CD38 inhibitors include (i) hydrogen bond and hydrophobic interactions with residues Glu226 and Trp125, (ii) electrostatic or hydrogen bond interaction with the positively charged residue Arg127 region, and (iii) the hydrophobic interaction with residue Trp189. For covalent inhibitors, besides the covalent effect with residue Glu226, the electrostatic interaction with residue Arg127 is also necessary, while another hydrogen/non-bonded interaction with residues Trp125 and Trp189 can also be detected. By means of the SYBYL multifit alignment function, the best CoMFA and CoMSIA with CD38 covalent inhibitors presented cross-validated correlation coefficient values (q(2)) of 0.564 and 0.571, and non-cross-validated values (r(2)) of 0.967 and 0.971, respectively. The CD38 non-covalent inhibitors can be classified into five groups according to their chemical scaffolds, and the residues Glu226, Trp189, and Trp125 are indispensable for those non-covalent inhibitors binding to CD38, while the residues Ser126, Arg127, Asp155, Thr221, and Phe222 are also important. The best CoMFA and CoMSIA with the F12 analogues presented cross-validated correlation coefficient values (q(2)) of 0.469 and 0.454, and non-cross-validated values (r(2)) of 0.814 and 0.819, respectively. © 2015 John Wiley & Sons A/S.

How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the αβ-Tubulin Colchicine Site

PubMed Central

Da, Chenxiao; Mooberry, Susan L.; Gupton, John T.; Kellogg, Glen E.

2013-01-01

αβ-tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q2 of 0.616, r2 of 0.949 and r2pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the ~3.6 Å available for αβ-tubulin. PMID:23961916

Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics

NASA Astrophysics Data System (ADS)

Debnath, Utsab; Verma, Saroj; Jain, Surabhi; Katti, Setu B.; Prabhakar, Yenamandra S.

2013-07-01

CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors' binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants' isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.

A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.

PubMed

Ding, Weimin; Sun, Miao; Luo, Shaman; Xu, Tao; Cao, Yibo; Yan, Xiufeng; Wang, Yang

2013-08-22

Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC₅₀ values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q² value of 0.722 and a non-cross-validation r² value of 0.974, which suggested that the model has good predictive ability (q² > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electron-withdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC₅₀ values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC₅₀ values were lower than those of BA in all cell lines, excluding DU145 cells.

Estimation of Remote Microclimates from Weather Station Data with Applications to Landscape Architecture.

NASA Astrophysics Data System (ADS)

Brown, Robert Douglas

Several components of a system for quantitative application of climatic statistics to landscape planning and design (CLIMACS) have been developed. One component model (MICROSIM) estimated the microclimate at the top of a remote crop using physically-based models and inputs of weather station data. Temperatures at the top of unstressed, uniform crops on flat terrain within 1600 m of a recording weather station were estimated within 1.0 C 96% of the time for a corn crop and 92% of the time for a soybean crop. Crop top winds were estimated within 0.4 m/s 92% of the time for corn and 100% of the time for soybean. This is of sufficient accuracy for application in landscape planning and design models. A physically-based model (COMFA) was developed for the determination of outdoor human thermal comfort from microclimate inputs. Estimated versus measured comfort levels in a wide range of environments agreed with a correlation coefficient of r = 0.91. Using these components, the CLIMACS concept has been applied to a typical planning example. Microclimate data were generated from weather station information using MICROSIM, then input to COMFA and to a house energy consumption model called HOTCAN to derive quantitative climatic justification for design decisions.

Integrated machine learning, molecular docking and 3D-QSAR based approach for identification of potential inhibitors of trypanosomal N-myristoyltransferase.

PubMed

Singh, Nidhi; Shah, Priyanka; Dwivedi, Hemlata; Mishra, Shikha; Tripathi, Renu; Sahasrabuddhe, Amogh A; Siddiqi, Mohammad Imran

2016-11-15

N-Myristoyltransferase (NMT) catalyzes the transfer of myristate to the amino-terminal glycine of a subset of proteins, a co-translational modification involved in trafficking substrate proteins to membrane locations, stabilization and protein-protein interactions. It is a studied and validated pre-clinical drug target for fungal and parasitic infections. In the present study, a machine learning approach, docking studies and CoMFA analysis have been integrated with the objective of translation of knowledge into a pipelined workflow towards the identification of putative hits through the screening of large compound libraries. In the proposed pipeline, the reported parasitic NMT inhibitors have been used to develop predictive machine learning classification models. Simultaneously, a TbNMT complex model was generated to establish the relationship between the binding mode of the inhibitors for LmNMT and TbNMT through molecular dynamics simulation studies. A 3D-QSAR model was developed and used to predict the activity of the proposed hits in the subsequent step. The hits classified as active based on the machine learning model were assessed as the potential anti-trypanosomal NMT inhibitors through molecular docking studies, predicted activity using a QSAR model and visual inspection. In the final step, the proposed pipeline was validated through in vitro experiments. A total of seven hits have been proposed and tested in vitro for evaluation of dual inhibitory activity against Leishmania donovani and Trypanosoma brucei. Out of these five compounds showed significant inhibition against both of the organisms. The common topmost active compound SEW04173 belongs to a pyrazole carboxylate scaffold and is anticipated to enrich the chemical space with enhanced potency through optimization.

Revealing interaction mode between HIV-1 protease and mannitol analog inhibitor.

PubMed

Yan, Guan-Wen; Chen, Yue; Li, Yixue; Chen, Hai-Feng

2012-06-01

HIV protease is a key enzyme to play a key role in the HIV-1 replication cycle and control the maturation from HIV viruses to an infectious virion. HIV-1 protease has become an important target for anti-HIV-1 drug development. Here, we used molecular dynamics simulation to study the binding mode between mannitol derivatives and HIV-1 protease. The results suggest that the most active compound (M35) has more stable hydrogen bonds and stable native contacts than the less active one (M17). These mannitol derivatives might have similar interaction mode with HIV-1 protease. Then, 3D-QSAR was used to construct quantitative structure-activity models. The cross-validated q(2) values are found as 0.728 and 0.611 for CoMFA and CoMSIA, respectively. And the non-cross-validated r(2) values are 0.973 and 0.950. Nine test set compounds validate the model. The results show that this model possesses better prediction ability than the previous work. This model can be used to design new chemical entities and make quantitative prediction of the bioactivities for HIV-1 protease inhibitors before resorting to in vitro and in vivo experiment. © 2012 John Wiley & Sons A/S.

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking.

PubMed

Prasanna, Sivaprakasam; Daga, Pankaj R; Xie, Aihua; Doerksen, Robert J

2009-02-01

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3alpha inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3alpha and GSK-3beta isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the beta isoform are the same in the alpha isoform, except that Asp133 in the beta isoform is replaced by Glu196 in the alpha isoform. We prepared a homology model for GSK-3alpha, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the beta isoform, and helped to explain the difference in their inhibitory activity.

Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking

NASA Astrophysics Data System (ADS)

Prasanna, Sivaprakasam; Daga, Pankaj R.; Xie, Aihua; Doerksen, Robert J.

2009-02-01

Glycogen synthase kinase-3, a serine/threonine kinase, has been implicated in a wide variety of pathological conditions such as diabetes, Alzheimer's disease, stroke, bipolar disorder, malaria and cancer. Herein we report 3D-QSAR analyses using CoMFA and CoMSIA and molecular docking studies on 3-anilino-4-phenylmaleimides as GSK-3α inhibitors, in order to better understand the mechanism of action and structure-activity relationship of these compounds. Comparison of the active site residues of GSK-3α and GSK-3β isoforms shows that all the key amino acids involved in polar interactions with the maleimides for the β isoform are the same in the α isoform, except that Asp133 in the β isoform is replaced by Glu196 in the α isoform. We prepared a homology model for GSK-3α, and showed that the change from Asp to Glu should not affect maleimide binding significantly. Docking studies revealed the binding poses of three subclasses of these ligands, namely anilino, N-methylanilino and indoline derivatives, within the active site of the β isoform, and helped to explain the difference in their inhibitory activity.

Development of predictive pharmacophore model for in silico screening, and 3D QSAR CoMFA and CoMSIA studies for lead optimization, for designing of potent tumor necrosis factor alpha converting enzyme inhibitors

NASA Astrophysics Data System (ADS)

Murumkar, Prashant Revan; Zambre, Vishal Prakash; Yadav, Mange Ram

2010-02-01

A chemical feature-based pharmacophore model was developed for Tumor Necrosis Factor-α converting enzyme (TACE) inhibitors. A five point pharmacophore model having two hydrogen bond acceptors (A), one hydrogen bond donor (D) and two aromatic rings (R) with discrete geometries as pharmacophoric features was developed. The pharmacophore model so generated was then utilized for in silico screening of a database. The pharmacophore model so developed was validated by using four compounds having proven TACE inhibitory activity which were grafted into the database. These compounds mapped well onto the five listed pharmacophoric features. This validated pharmacophore model was also used for alignment of molecules in CoMFA and CoMSIA analysis. The contour maps of the CoMFA/CoMSIA models were utilized to provide structural insight for activity improvement of potential novel TACE inhibitors. The pharmacophore model so developed could be used for in silico screening of any commercial/in house database for identification of TACE inhibiting lead compounds, and the leads so identified could be optimized using the developed CoMSIA model. The present work highlights the tremendous potential of the two mutually complementary ligand-based drug designing techniques (i.e. pharmacophore mapping and 3D-QSAR analysis) using TACE inhibitors as prototype biologically active molecules.

Comparison of human radiation exchange models in outdoor areas

NASA Astrophysics Data System (ADS)

Park, Sookuk; Tuller, Stanton E.

2011-10-01

Results from the radiation components of seven different human thermal exchange models/methods are compared. These include the Burt, COMFA, MENEX, OUT_SET* and RayMan models, the six-directional method and the new Park and Tuller model employing projected area factors ( f p) and effective radiation area factors ( f eff) determined from a sample of normal- and over-weight Canadian Caucasian adults. Input data include solar and longwave radiation measured during a clear summer day in southern Ontario. Variations between models came from differences in f p and f eff and different estimates of longwave radiation from the open sky. The ranges between models for absorbed solar, net longwave and net all-wave radiation were 164, 31 and 187 W m-2, respectively. These differentials between models can be significant in total human thermal exchange. Therefore, proper f p and f eff values should be used to make accurate estimation of radiation on the human body surface.

Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists

PubMed Central

Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

2011-01-01

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson’s disease and schizophrenia. Herein, we report the three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [3H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q2 of 0.513, R2 ncv of 0.868, R2 pred = 0.876, while the CoMSIA model yielded a Q2 of 0.450, R2 ncv = 0.899, R2 pred = 0.735. For activity II study, CoMFA model yielded statistics of Q2 = 0.5, R2 ncv = 0.715, R2 pred = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R7, R3 and position A benefit activity I of the antagonists, but decrease it when projected in R8 and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists. PMID:22016641

Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists.

PubMed

Zhang, Meng-Qi; Zhang, Xiao-Le; Li, Yan; Fan, Wen-Jia; Wang, Yong-Hua; Hao, Ming; Zhang, Shu-Wei; Ai, Chun-Zhi

2011-01-01

MGluR2 is G protein-coupled receptor that is targeted for diseases like anxiety, depression, Parkinson's disease and schizophrenia. Herein, we report the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of a series of 1,3-dihydrobenzo[ b][1,4]diazepin-2-one derivatives as mGluR2 antagonists. Two series of models using two different activities of the antagonists against rat mGluR2, which has been shown to be very similar to the human mGluR2, (activity I: inhibition of [(3)H]-LY354740; activity II: mGluR2 (1S,3R)-ACPD inhibition of forskolin stimulated cAMP.) were derived from datasets composed of 137 and 69 molecules respectively. For activity I study, the best predictive model obtained from CoMFA analysis yielded a Q(2) of 0.513, R(2) (ncv) of 0.868, R(2) (pred) = 0.876, while the CoMSIA model yielded a Q(2) of 0.450, R(2) (ncv) = 0.899, R(2) (pred) = 0.735. For activity II study, CoMFA model yielded statistics of Q(2) = 0.5, R(2) (ncv) = 0.715, R(2) (pred) = 0.723. These results prove the high predictability of the models. Furthermore, a combined analysis between the CoMFA, CoMSIA contour maps shows that: (1) Bulky substituents in R(7), R(3) and position A benefit activity I of the antagonists, but decrease it when projected in R(8) and position B; (2) Hydrophilic groups at position A and B increase both antagonistic activity I and II; (3) Electrostatic field plays an essential rule in the variance of activity II. In search for more potent mGluR2 antagonists, two pharmacophore models were developed separately for the two activities. The first model reveals six pharmacophoric features, namely an aromatic center, two hydrophobic centers, an H-donor atom, an H-acceptor atom and an H-donor site. The second model shares all features of the first one and has an additional acceptor site, a positive N and an aromatic center. These models can be used as guidance for the development of new mGluR2 antagonists of high activity and selectivity. This work is the first report on 3D-QSAR modeling of these mGluR2 antagonists. All the conclusions may lead to a better understanding of the mechanism of antagonism and be helpful in the design of new potent mGluR2 antagonists.

First report on 3D-QSAR and molecular dynamics based docking studies of GCPII inhibitors for targeted drug delivery applications

NASA Astrophysics Data System (ADS)

Pandit, Amit; Sengupta, Sagnik; Krishnan, Mena Asha; Reddy, Ramesh B.; Sharma, Rajesh; Venkatesh, Chelvam

2018-05-01

Prostate Specific Membrane Antigen (PSMA) or Glutamate carboxypeptidase II (GCPII) has been identified as an important target in diagnosis and therapy of prostate cancer. Among several types of inhibitors, urea based inhibitors are the most common and widely employed in preclinical and clinical studies. Computational studies have been carried out to uncover active sites and interaction of PSMA inhibitors with the protein by modifying the core structure of the ligand. Analysis of the literature, however, show lack of 3-D quantitative structure activity relationship (QSAR) and molecular dynamics based molecular docking study to identify structural modifications responsible for better GCPII inhibitory activity. The present study aims to fulfil this gap by analysing well known PSMA inhibitors reported in the literature with known experimental PSMA inhibition constants. Also in order to validate the in silico study, a new GCPII inhibitor 7 was designed, synthesized and experimental PSMA enzyme inhibition was evaluated by using freshly isolated PSMA protein from human cancer cell line derived from lymph node, LNCaP. 3D-QSAR CoMFA models on 58 urea based GCPII inhibitors were generated, and the best correlation was obtained in Gast-Huck charge assigning method with q2, r2 and predictive r2 values as 0.592, 0.995 and 0.842 respectively. Moreover, steric, electrostatic, and hydrogen bond donor field contribution analysis provided best statistical values from CoMSIA model (q2, r2 and predictive r2 as 0.527, 0.981 and 0.713 respectively). Contour maps study revealed that electrostatic field contribution is the major factor for discovering better binding affinity ligands. Further molecular dynamic assisted molecular docking was also performed on GCPII receptor (PDB ID 4NGM) and most active GCPII inhibitor, DCIBzL. 4NGM co-crystallised ligand, JB7 was used to validate the docking procedure and the amino acid interactions present in JB7 are compared with DCIBzL. The results suggest that Arg210, Asn257, Gly518, Tyr552, Lys699, and Tyr700 amino acid residues may play a crucial role in GCPII inhibition. Molecular Dynamics Simulation provides information about docked pose stability of DCIBzL. By combination of CoMFA-CoMSIA field analysis and docking interaction analysis studies, conclusive SAR was generated for urea based derivatives based on which GCPII inhibitor 7 was designed and chemically synthesized in our laboratory. Evaluation of GCPII inhibitory activity of 7 by performing NAALADase assay provided IC50 value of 113 nM which is in close agreement with in silico predicted value (119 nM). Thus we have successfully validated our 3D-QSAR and molecular docking based designing of GCPII inhibitors methodology through biological experiments. This conclusive SAR would be helpful to generate novel and more potent GCPII inhibitors for drug delivery applications.

Development of a pharmacophore for cruzain using oxadiazoles as virtual molecular probes: quantitative structure-activity relationship studies

NASA Astrophysics Data System (ADS)

de Souza, Anacleto S.; de Oliveira, Marcelo T.; Andricopulo, Adriano D.

2017-09-01

Chagas's is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi. According to the World Health Organization, 7 million people are infected worldwide leading to 7000 deaths per year. Drugs available, nifurtimox and benzimidazole, are limited due to low efficacy and high toxicity. As a validated target, cruzain represents a major front in drug discovery attempts for Chagas disease. Herein, we describe the development of 2D QSAR (r_{{{pred}}}2 = 0.81) and a 3D-QSAR-based pharmacophore (r_{{{pred}}}2 = 0.82) from a series of non-covalent cruzain inhibitors represented mostly by oxadiazoles (lead compound, IC50 = 200 nM). Both models allowed us to map key intermolecular interactions in S1', S2 and S3 cruzain sub-sites (including halogen bond and C‒H/π). To probe the predictive capacity of obtained models, inhibitors available in the literature from different classes displaying a range of scaffolds were evaluate achieving mean absolute deviation of 0.33 and 0.51 for 2D and 3D models, respectively. CoMFA revealed an unexplored region where addition of bulky substituents to produce new compounds in the series could be beneficial to improve biological activity.

A comparison of progestin and androgen receptor binding using the CoMFA technique

NASA Astrophysics Data System (ADS)

Loughney, Deborah A.; Schwender, Charles F.

1992-12-01

A series of 48 steroids has been studied with the SYBYL QSAR module using Relative Binding Affinities (RBAs) to progesterone and androgen receptors obtained from the literature. Models for the progesterone and androgen data were developed. Both models show regions where sterics and electrostatics correlate to binding affinity but are different for androgen and progesterone which suggests differences possibly important for receptor selectivity. The progesterone model is more predictive than the androgen (predictive r2 of 0.725 vs. 0.545 for progesterone and androgen, respectively).

Application of 3D-QSAR in the rational design of receptor ligands and enzyme inhibitors.

PubMed

Mor, Marco; Rivara, Silvia; Lodola, Alessio; Lorenzi, Simone; Bordi, Fabrizio; Plazzi, Pier Vincenzo; Spadoni, Gilberto; Bedini, Annalida; Duranti, Andrea; Tontini, Andrea; Tarzia, Giorgio

2005-11-01

Quantitative structure-activity relationships (QSARs) are frequently employed in medicinal chemistry projects, both to rationalize structure-activity relationships (SAR) for known series of compounds and to help in the design of innovative structures endowed with desired pharmacological actions. As a difference from the so-called structure-based drug design tools, they do not require the knowledge of the biological target structure, but are based on the comparison of drug structural features, thus being defined ligand-based drug design tools. In the 3D-QSAR approach, structural descriptors are calculated from molecular models of the ligands, as interaction fields within a three-dimensional (3D) lattice of points surrounding the ligand structure. These descriptors are collected in a large X matrix, which is submitted to multivariate analysis to look for correlations with biological activity. Like for other QSARs, the reliability and usefulness of the correlation models depends on the validity of the assumptions and on the quality of the data. A careful selection of compounds and pharmacological data can improve the application of 3D-QSAR analysis in drug design. Some examples of the application of CoMFA and CoMSIA approaches to the SAR study and design of receptor or enzyme ligands is described, pointing the attention to the fields of melatonin receptor ligands and FAAH inhibitors.

LQTA-QSAR: a new 4D-QSAR methodology.

PubMed

Martins, João Paulo A; Barbosa, Euzébio G; Pasqualoto, Kerly F M; Ferreira, Márcia M C

2009-06-01

A novel 4D-QSAR approach which makes use of the molecular dynamics (MD) trajectories and topology information retrieved from the GROMACS package is presented in this study. This new methodology, named LQTA-QSAR (LQTA, Laboratório de Quimiometria Teórica e Aplicada), has a module (LQTAgrid) that calculates intermolecular interaction energies at each grid point considering probes and all aligned conformations resulting from MD simulations. These interaction energies are the independent variables or descriptors employed in a QSAR analysis. The comparison of the proposed methodology to other 4D-QSAR and CoMFA formalisms was performed using a set of forty-seven glycogen phosphorylase b inhibitors (data set 1) and a set of forty-four MAP p38 kinase inhibitors (data set 2). The QSAR models for both data sets were built using the ordered predictor selection (OPS) algorithm for variable selection. Model validation was carried out applying y-randomization and leave-N-out cross-validation in addition to the external validation. PLS models for data set 1 and 2 provided the following statistics: q(2) = 0.72, r(2) = 0.81 for 12 variables selected and 2 latent variables and q(2) = 0.82, r(2) = 0.90 for 10 variables selected and 5 latent variables, respectively. Visualization of the descriptors in 3D space was successfully interpreted from the chemical point of view, supporting the applicability of this new approach in rational drug design.

First report on the structural exploration and prediction of new BPTES analogs as glutaminase inhibitors

NASA Astrophysics Data System (ADS)

Amin, Sk. Abdul; Adhikari, Nilanjan; Gayen, Shovanlal; Jha, Tarun

2017-09-01

Glutaminase is one of the important key enzymes regulating cellular metabolism, growth, and proliferation in cancer. Therefore, it is being explored as a crucial target regarding anticancer drug design and development. However, none of the potent and selective glutaminase inhibitors is available in the market though two prototype glutaminase inhibitors are reported namely DON as well as BPTES. Due to severe toxicity in clinical trials, the use of DON is restricted. However, BPTES is an allosteric glutaminase inhibitor with less toxic profile and, therefore, lead optimization of BPTES may be a good option to develop newer drug candidates. In this study, a multi-QSAR modeling is carried out on a series of BPTES analogs. A significant connection between different descriptors and the glutaminase inhibitory activities is noticed by employing multiple linear regression, artificial neural network and support vector machine techniques. The classification-based QSAR such as linear discriminant analysis and Bayesian classification modeling are also performed to search important molecular fingerprints or substructures that may help in classifying the probability of finding 'active' and 'inactive' BPTES analogs. Moreover, HQSAR and Topomer CoMFA analyses are also performed. In addition, the SAR observations are interpreted with all these validated computational models along with the structure-based contours. Finally, new twenty two compounds are designed and predicted for their probable glutaminase inhibitory activity.

A general approach for developing system-specific functions to score protein-ligand docked complexes using support vector inductive logic programming.

PubMed

Amini, Ata; Shrimpton, Paul J; Muggleton, Stephen H; Sternberg, Michael J E

2007-12-01

Despite the increased recent use of protein-ligand and protein-protein docking in the drug discovery process due to the increases in computational power, the difficulty of accurately ranking the binding affinities of a series of ligands or a series of proteins docked to a protein receptor remains largely unsolved. This problem is of major concern in lead optimization procedures and has lead to the development of scoring functions tailored to rank the binding affinities of a series of ligands to a specific system. However, such methods can take a long time to develop and their transferability to other systems remains open to question. Here we demonstrate that given a suitable amount of background information a new approach using support vector inductive logic programming (SVILP) can be used to produce system-specific scoring functions. Inductive logic programming (ILP) learns logic-based rules for a given dataset that can be used to describe properties of each member of the set in a qualitative manner. By combining ILP with support vector machine regression, a quantitative set of rules can be obtained. SVILP has previously been used in a biological context to examine datasets containing a series of singular molecular structures and properties. Here we describe the use of SVILP to produce binding affinity predictions of a series of ligands to a particular protein. We also for the first time examine the applicability of SVILP techniques to datasets consisting of protein-ligand complexes. Our results show that SVILP performs comparably with other state-of-the-art methods on five protein-ligand systems as judged by similar cross-validated squares of their correlation coefficients. A McNemar test comparing SVILP to CoMFA and CoMSIA across the five systems indicates our method to be significantly better on one occasion. The ability to graphically display and understand the SVILP-produced rules is demonstrated and this feature of ILP can be used to derive hypothesis for future ligand design in lead optimization procedures. The approach can readily be extended to evaluate the binding affinities of a series of protein-protein complexes. (c) 2007 Wiley-Liss, Inc.

Virtual screening and rational drug design method using structure generation system based on 3D-QSAR and docking.

PubMed

Chen, H F; Dong, X C; Zen, B S; Gao, K; Yuan, S G; Panaye, A; Doucet, J P; Fan, B T

2003-08-01

An efficient virtual and rational drug design method is presented. It combines virtual bioactive compound generation with 3D-QSAR model and docking. Using this method, it is possible to generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study of a set of anti-tumor drugs. With the constraints of pharmacophore obtained by DISCO implemented in SYBYL 6.8, 97 virtual bioactive compounds were generated, and their anti-tumor activities were predicted by CoMFA. Eight structures with high activity were selected and screened by the 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity. A comparative docking study with telomeric receptor was carried out, and the results showed that the generated structures could form more stable complexes with receptor than the reference compound selected from experimental data. This investigation showed that the proposed method was a feasible way for rational drug design with high screening efficiency.

3D-QSAR studies of some reversible Acetyl cholinesterase inhibitors based on CoMFA and ligand protein interaction fingerprints using PC-LS-SVM and PLS-LS-SVM.

PubMed

Ghafouri, Hamidreza; Ranjbar, Mohsen; Sakhteman, Amirhossein

2017-08-01

A great challenge in medicinal chemistry is to develop different methods for structural design based on the pattern of the previously synthesized compounds. In this study two different QSAR methods were established and compared for a series of piperidine acetylcholinesterase inhibitors. In one novel approach, PC-LS-SVM and PLS-LS-SVM was used for modeling 3D interaction descriptors, and in the other method the same nonlinear techniques were used to build QSAR equations based on field descriptors. Different validation methods were used to evaluate the models and the results revealed the more applicability and predictive ability of the model generated by field descriptors (Q 2 LOO-CV =1, R 2 ext =0.97). External validation criteria revealed that both methods can be used in generating reasonable QSAR models. It was concluded that due to ability of interaction descriptors in prediction of binding mode, using this approach can be implemented in future 3D-QSAR softwares. Copyright © 2017 Elsevier Ltd. All rights reserved.

3D-QSAR studies on 1,2,4-triazolyl 5-azaspiro [2.4]-heptanes as D3R antagonists

NASA Astrophysics Data System (ADS)

Zhang, Xin; Zhang, Hui

2018-07-01

Dopamine D3 receptor has become an attractive target in the treatment of abused drugs. 3D-QSAR studies were performed on a novel series of D3 receptor antagonists, 1,2,4-triazolyl 5-azaspiro [2.4]-heptanes, using CoMFA and CoMSIA methods. Two predictive 3D-QSAR models have been generated for the modified design of D3R antagonists. Based on the steric, electrostatic, hydrophobic and hydrogen-bond acceptor information of contour maps, key structural factors affecting the bioactivity were explored. This work gives helpful suggestions on the design of novel D3R antagonists with increased activities.

Grid-based Continual Analysis of Molecular Interior for Drug Discovery, QSAR and QSPR.

PubMed

Potemkin, Andrey V; Grishina, Maria A; Potemkin, Vladimir A

2017-01-01

In 1979, R.D.Cramer and M.Milne made a first realization of 3D comparison of molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (Dynamic Lattice- Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988, the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules. A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) are invented in the current paper. The grid-based analysis is fulfilled by means of a lattice construction analogously to many other grid-based methods. The further continual elucidation of molecular structure is performed in various ways. (i) In terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. All the functions can be calculated using a quantum approach at a sufficient level of theory and their values can be determined in all lattice points for a molecule. Then, the molecules of a dataset can be superimposed in the lattice for the maximal coincidence (or minimal deviations) of the potentials (i) or the quantum functions (ii). The methods and criteria of the superimposition are discussed. After that a functional relationship between biological activity or property and characteristics of potentials (i) or functions (ii) is created. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page. Therefore, a set of 3D QSAR approaches for continual molecular interior study giving a lot of opportunities for virtual drug discovery, virtual screening and ligand-based drug design are invented. The continual elucidation of molecular structure is performed in the terms of intermolecular interactions potentials and in the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the first principles, an original quantum free-orbital approach AlteQ is proposed. The methods of the quantitative relationship construction are discussed. New approaches for rational virtual drug design based on the intermolecular potentials and quantum functions are invented. All the invented methods are realized at www.chemosophia.com web page. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Discovery and quantitative structure-activity relationship study of lepidopteran HMG-CoA reductase inhibitors as selective insecticides.

PubMed

Zang, Yang-Yang; Li, Yuan-Mei; Yin, Yue; Chen, Shan-Shan; Kai, Zhen-Peng

2017-09-01

In a previous study we have demonstrated that insect 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) can be a potential selective insecticide target. Three series of inhibitors were designed on the basis of the difference in HMGR structures from Homo sapiens and Manduca sexta, with the aim of discovering potent selective insecticide candidates. An in vitro bioassay showed that gem-difluoromethylenated statin analogues have potent effects on JH biosynthesis of M. sexta and high selectivity between H. sapiens and M. sexta. All series II compounds {1,3,5-trisubstituted [4-tert-butyl 2-(5,5-difluoro-2,2-dimethyl-6-vinyl-4-yl) acetate] pyrazoles} have some effect on JH biosynthesis, whereas most of them are inactive on human HMGR. In particular, the IC 50 value of compound II-12 (37.8 nm) is lower than that of lovastatin (99.5 nm) and similar to that of rosuvastatin (24.2 nm). An in vivo bioassay showed that I-1, I-2, I-3 and II-12 are potential selective insecticides, especially for lepidopteran pest control. A predictable and statistically meaningful CoMFA model of 23 inhibitors (20 as training sets and three as test sets) was obtained with a value of q 2 and r 2 of 0.66 and 0.996 respectively. The final model suggested that a potent insect HMGR inhibitor should contain suitable small and non-electronegative groups in the ring part, and electronegative groups in the side chain. Four analogues were discovered as potent selective lepidopteran HMGR inhibitors, which can specifically be used for lepidopteran pest control. The CoMFA model will be useful for the design of new selective insect HMGR inhibitors that are structurally related to the training set compounds. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Receptor-based 3D QSAR analysis of estrogen receptor ligands - merging the accuracy of receptor-based alignments with the computational efficiency of ligand-based methods

NASA Astrophysics Data System (ADS)

Sippl, Wolfgang

2000-08-01

One of the major challenges in computational approaches to drug design is the accurate prediction of binding affinity of biomolecules. In the present study several prediction methods for a published set of estrogen receptor ligands are investigated and compared. The binding modes of 30 ligands were determined using the docking program AutoDock and were compared with available X-ray structures of estrogen receptor-ligand complexes. On the basis of the docking results an interaction energy-based model, which uses the information of the whole ligand-receptor complex, was generated. Several parameters were modified in order to analyze their influence onto the correlation between binding affinities and calculated ligand-receptor interaction energies. The highest correlation coefficient ( r 2 = 0.617, q 2 LOO = 0.570) was obtained considering protein flexibility during the interaction energy evaluation. The second prediction method uses a combination of receptor-based and 3D quantitative structure-activity relationships (3D QSAR) methods. The ligand alignment obtained from the docking simulations was taken as basis for a comparative field analysis applying the GRID/GOLPE program. Using the interaction field derived with a water probe and applying the smart region definition (SRD) variable selection, a significant and robust model was obtained ( r 2 = 0.991, q 2 LOO = 0.921). The predictive ability of the established model was further evaluated by using a test set of six additional compounds. The comparison with the generated interaction energy-based model and with a traditional CoMFA model obtained using a ligand-based alignment ( r 2 = 0.951, q 2 LOO = 0.796) indicates that the combination of receptor-based and 3D QSAR methods is able to improve the quality of the underlying model.

Computer-aided design, synthesis and biological assay of p-methylsulfonamido phenylethylamine analogues.

PubMed

Liu, H; Ji, M; Jiang, H; Liu, L; Hua, W; Chen, K; Ji, R

2000-10-02

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Based on our previous studies, a set of 17 methylsulfonamido phenylethylamine analogues were investigated by 3D-QSAR techniques of CoMFA and CoMSIA. The 3D-QSAR models proved a good predictive ability, and could describe the steric, electrostatic and hydrophobic requirements for recognition forces of the receptor site. According to the clues provided by this 3D-QSAR analysis, we designed and synthesized a series of new analogues of methanesulfonamido phenylethylamine (VIa-i). Pharmacological assay indicated that the effective concentrations of delaying the functional refractory period (FRP) 10ms of these new compounds have a good correlation with the 3D-QSAR predicted values. It is remarkable that the maximal percent change of delaying FRP in microM of compound VIc is much higher than that of dofetilide. The results showed that the 3D-QSAR models are reliable.

Evaluation of designed ligands by a multiple screening method: Application to glycogen phosphorylase inhibitors constructed with a variety of approaches

NASA Astrophysics Data System (ADS)

So, Sung-Sau; Karplus, Martin

2001-07-01

Glycogen phosphorylase (GP) is an important enzyme that regulates blood glucose level and a key therapeutic target for the treatment of type II diabetes. In this study, a number of potential GP inhibitors are designed with a variety of computational approaches. They include the applications of MCSS, LUDI and CoMFA to identify additional fragments that can be attached to existing lead molecules; the use of 2D and 3D similarity-based QSAR models (HQSAR and SMGNN) and of the LUDI program to identify novel molecules that may bind to the glucose binding site. The designed ligands are evaluated by a multiple screening method, which is a combination of commercial and in-house ligand-receptor binding affinity prediction programs used in a previous study (So and Karplus, J. Comp.-Aid. Mol. Des., 13 (1999), 243-258). Each method is used at an appropriate point in the screening, as determined by both the accuracy of the calculations and the computational cost. A comparison of the strengths and weaknesses of the ligand design approaches is made.

Design and synthesis of N-(3,3-diphenylpropenyl)alkanamides as a novel class of high-affinity MT2-selective melatonin receptor ligands.

PubMed

Bedini, Annalida; Spadoni, Gilberto; Gatti, Giuseppe; Lucarini, Simone; Tarzia, Giorgio; Rivara, Silvia; Lorenzi, Simone; Lodola, Alessio; Mor, Marco; Lucini, Valeria; Pannacci, Marilou; Scaglione, Francesco

2006-12-14

A novel series of melatonin receptor ligands was discovered by opening the cyclic scaffolds of known classes of high affinity melatonin receptor antagonists, while retaining the pharmacophore elements postulated by previously described 3D-QSAR and receptor models. Compounds belonging to the classes of 2,3- and [3,3-diphenylprop(en)yl]alkanamides and of o- or [(m-benzyl)phenyl]ethyl-alkanamides were synthesized and tested on MT(1) and MT(2) receptors. The class of 3,3-diphenyl-propenyl-alkanamides was the most interesting one, with compounds having MT(2) receptor affinity similar to that of MLT, remarkable MT(2) selectivity, and partial agonist or antagonist behavior. In particular, the (E)-m-methoxy cyclobutanecarboxamido derivative 18f and the di-(m-methoxy) acetamido one, 18g, have sub-nM affinity for the MT(2) subtype, with more than 100-fold selectivity over MT(1), 18f being an antagonist and 18g a partial agonist on GTPgammaS test. Docking of 18g into a previously developed MT(2) receptor model showed a binding scheme consistent with that of other antagonists. The MT(2) expected binding affinities of the new compounds were calculated by a previously developed 3D-QSAR CoMFA model, giving satisfactory predictions.

Viscoelastic properties of dendrimers in the melt from nonequlibrium molecular dynamics

NASA Astrophysics Data System (ADS)

Bosko, Jaroslaw T.; Todd, B. D.; Sadus, Richard J.

2004-12-01

The viscoelastic properties of dendrimers of generation 1-4 are studied using nonequilibrium molecular dynamics. Flow properties of dendrimer melts under shear are compared to systems composed of linear chain polymers of the same molecular weight, and the influence of molecular architecture is discussed. Rheological material properties, such as the shear viscosity and normal stress coefficients, are calculated and compared for both systems. We also calculate and compare the microscopic properties of both linear chain and dendrimer molecules, such as their molecular alignment, order parameters and rotational velocities. We find that the highly symmetric shape of dendrimers and their highly constrained geometry allows for substantial differences in their material properties compared to traditional linear polymers of equivalent molecular weight.

A Comparison of Molecular Vibrational Theory to Huckel Molecular Orbital Theory.

ERIC Educational Resources Information Center

Keeports, David

1986-01-01

Compares the similar mathematical problems of molecular vibrational calculations (at any intermediate level of sophistication) and molecular orbital calculations (at the Huckel level). Discusses how the generalizations of Huckel treatment of molecular orbitals apply to vibrational theory. (TW)

3D-quantitative structure-activity relationship studies on benzothiadiazepine hydroxamates as inhibitors of tumor necrosis factor-alpha converting enzyme.

PubMed

Murumkar, Prashant R; Giridhar, Rajani; Yadav, Mange Ram

2008-04-01

A set of 29 benzothiadiazepine hydroxamates having selective tumor necrosis factor-alpha converting enzyme inhibitory activity were used to compare the quality and predictive power of 3D-quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices models for the atom-based, centroid/atom-based, data-based, and docked conformer-based alignment. Removal of two outliers from the initial training set of molecules improved the predictivity of models. Among the 3D-quantitative structure-activity relationship models developed using the above four alignments, the database alignment provided the optimal predictive comparative molecular field analysis model for the training set with cross-validated r(2) (q(2)) = 0.510, non-cross-validated r(2) = 0.972, standard error of estimates (s) = 0.098, and F = 215.44 and the optimal comparative molecular similarity indices model with cross-validated r(2) (q(2)) = 0.556, non-cross-validated r(2) = 0.946, standard error of estimates (s) = 0.163, and F = 99.785. These models also showed the best test set prediction for six compounds with predictive r(2) values of 0.460 and 0.535, respectively. The contour maps obtained from 3D-quantitative structure-activity relationship studies were appraised for activity trends for the molecules analyzed. The comparative molecular similarity indices models exhibited good external predictivity as compared with that of comparative molecular field analysis models. The data generated from the present study helped us to further design and report some novel and potent tumor necrosis factor-alpha converting enzyme inhibitors.

Realization of Molecular-Based Transistors.

PubMed

Richter, Shachar; Mentovich, Elad; Elnathan, Roey

2018-06-06

Molecular-based devices are widely considered as significant candidates to play a role in the next generation of "post-complementary metal-oxide-semiconductor" devices. In this context, molecular-based transistors: molecular junctions that can be electrically gated-are of particular interest as they allow new modes of operation. The properties of molecular transistors composed of a single- or multimolecule assemblies, focusing on their practicality as real-world devices, concerning industry demands and its roadmap are compared. Also, the capability of the gate electrode to modulate the molecular transistor characteristics efficiently is addressed, showing that electrical gating can be easily facilitated in single molecular transistors and that gating of transistor composed of molecular assemblies is possible if the device is formed vertically. It is concluded that while the single-molecular transistor exhibits better performance on the lab-scale, its realization faces signifacant challenges when compared to those faced by transistors composed of a multimolecule assembly. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

2D- and 3D-quantitative structure-activity relationship studies for a series of phenazine N,N'-dioxide as antitumour agents.

PubMed

Cunha, Jonathan Da; Lavaggi, María Laura; Abasolo, María Inés; Cerecetto, Hugo; González, Mercedes

2011-12-01

Hypoxic regions of tumours are associated with increased resistance to radiation and chemotherapy. Nevertheless, hypoxia has been used as a tool for specific activation of some antitumour prodrugs, named bioreductive agents. Phenazine dioxides are an example of such bioreductive prodrugs. Our 2D-quantitative structure activity relationship studies established that phenazine dioxides electronic and lipophilic descriptors are related to survival fraction in oxia or in hypoxia. Additionally, statistically significant models, derived by partial least squares, were obtained between survival fraction in oxia and comparative molecular field analysis standard model (r² = 0.755, q² = 0.505 and F = 26.70) or comparative molecular similarity indices analysis-combined steric and electrostatic fields (r² = 0.757, q² = 0.527 and F = 14.93), and survival fraction in hypoxia and comparative molecular field analysis standard model (r² = 0.736, q² = 0.521 and F = 18.63) or comparative molecular similarity indices analysis-hydrogen bond acceptor field (r² = 0.858, q² = 0.737 and F = 27.19). Categorical classification was used for the biological parameter selective cytotoxicity emerging also good models, derived by soft independent modelling of class analogy, with both comparative molecular field analysis standard model (96% of overall classification accuracy) and comparative molecular similarity indices analysis-steric field (92% of overall classification accuracy). 2D- and 3D-quantitative structure-activity relationships models provided important insights into the chemical and structural basis involved in the molecular recognition process of these phenazines as bioreductive agents and should be useful for the design of new structurally related analogues with improved potency. © 2011 John Wiley & Sons A/S.

Suitability of different comfort indices for the prediction of thermal conditions in tree-covered outdoor spaces in arid cities

NASA Astrophysics Data System (ADS)

Ruiz, María Angélica; Correa, Erica Norma

2015-10-01

Outdoor thermal comfort is one of the most influential factors in the habitability of a space. Thermal level is defined not only by climate variables but also by the adaptation of people to the environment. This study presents a comparison between inductive and deductive thermal comfort models, contrasted with subjective reports, in order to identify which of the models can be used to most correctly predict thermal comfort in tree-covered outdoor spaces of the Mendoza Metropolitan Area, an intensely forested and open city located in an arid zone. Interviews and microclimatic measurements were carried out in winter 2010 and in summer 2011. Six widely used indices were selected according to different levels of complexity: the Temperature-Humidity Index (THI), Vinje's Comfort Index (PE), Thermal Sensation Index (TS), the Predicted Mean Vote (PMV), the COMFA model's energy balance (S), and the Physiological Equivalent Temperature (PET). The results show that the predictive models evaluated show percentages of predictive ability lower than 25 %. Despite this low indicator, inductive methods are adequate for obtaining a diagnosis of the degree and frequency in which a space is comfortable or not whereas deductive methods are recommended to influence urban design strategies. In addition, it is necessary to develop local models to evaluate perceived thermal comfort more adequately. This type of tool is very useful in the design and evaluation of the thermal conditions in outdoor spaces, based not only to climatic criteria but also subjective sensations.

A comparative cellular and molecular biology of longevity database.

PubMed

Stuart, Jeffrey A; Liang, Ping; Luo, Xuemei; Page, Melissa M; Gallagher, Emily J; Christoff, Casey A; Robb, Ellen L

2013-10-01

Discovering key cellular and molecular traits that promote longevity is a major goal of aging and longevity research. One experimental strategy is to determine which traits have been selected during the evolution of longevity in naturally long-lived animal species. This comparative approach has been applied to lifespan research for nearly four decades, yielding hundreds of datasets describing aspects of cell and molecular biology hypothesized to relate to animal longevity. Here, we introduce a Comparative Cellular and Molecular Biology of Longevity Database, available at ( http://genomics.brocku.ca/ccmbl/ ), as a compendium of comparative cell and molecular data presented in the context of longevity. This open access database will facilitate the meta-analysis of amalgamated datasets using standardized maximum lifespan (MLSP) data (from AnAge). The first edition contains over 800 data records describing experimental measurements of cellular stress resistance, reactive oxygen species metabolism, membrane composition, protein homeostasis, and genome homeostasis as they relate to vertebrate species MLSP. The purpose of this review is to introduce the database and briefly demonstrate its use in the meta-analysis of combined datasets.

Equilibrium Structures and Absorption Spectra for SixOy Molecular Clusters using Density Functional Theory

DTIC Science & Technology

2017-05-05

dependent density functional theory (TD-DFT). The size of the clusters considered is relatively large compared to those considered in previous studies...are characterized by many different geometries, which potentially can be optimized with respect to specific materials design criteria, i.e., molecular...SixOy molecular clusters using density functional theory (DFT). The size of the clusters considered, however, is relatively large compared to those

Graph-drawing algorithms geometries versus molecular mechanics in fullereness

NASA Astrophysics Data System (ADS)

Kaufman, M.; Pisanski, T.; Lukman, D.; Borštnik, B.; Graovac, A.

1996-09-01

The algorithms of Kamada-Kawai (KK) and Fruchterman-Reingold (FR) have been recently generalized (Pisanski et al., Croat. Chem. Acta 68 (1995) 283) in order to draw molecular graphs in three-dimensional space. The quality of KK and FR geometries is studied here by comparing them with the molecular mechanics (MM) and the adjacency matrix eigenvectors (AME) algorithm geometries. In order to compare different layouts of the same molecule, an appropriate method has been developed. Its application to a series of experimentally detected fullerenes indicates that the KK, FR and AME algorithms are able to reproduce plausible molecular geometries.

Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods.

PubMed

Fidler, Samantha; D'Orsogna, Lloyd; Irish, Ashley B; Lewis, Joshua R; Wong, Germaine; Lim, Wai H

2018-03-02

Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, which requires the entry of four-digit alleles. The aim of this study was to evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing. In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined. Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95% CI] 0.960-0.975) and 0.926 (95% CI 0.899-0.944), respectively; and 0.995 (95% CI 0.994-0.996) and 0.993 (95% CI 0.991-0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and 0% and 2% for two-digit versus four-digit molecular typing methods, respectively. In this small predominantly Caucasian population, compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two-compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation.

Global analysis of the yeast lipidome by quantitative shotgun mass spectrometry.

PubMed

Ejsing, Christer S; Sampaio, Julio L; Surendranath, Vineeth; Duchoslav, Eva; Ekroos, Kim; Klemm, Robin W; Simons, Kai; Shevchenko, Andrej

2009-02-17

Although the transcriptome, proteome, and interactome of several eukaryotic model organisms have been described in detail, lipidomes remain relatively uncharacterized. Using Saccharomyces cerevisiae as an example, we demonstrate that automated shotgun lipidomics analysis enabled lipidome-wide absolute quantification of individual molecular lipid species by streamlined processing of a single sample of only 2 million yeast cells. By comparative lipidomics, we achieved the absolute quantification of 250 molecular lipid species covering 21 major lipid classes. This analysis provided approximately 95% coverage of the yeast lipidome achieved with 125-fold improvement in sensitivity compared with previous approaches. Comparative lipidomics demonstrated that growth temperature and defects in lipid biosynthesis induce ripple effects throughout the molecular composition of the yeast lipidome. This work serves as a resource for molecular characterization of eukaryotic lipidomes, and establishes shotgun lipidomics as a powerful platform for complementing biochemical studies and other systems-level approaches.

Reaction Analysis of Shocked Nitromethane using Extended Lagrangian Born-Oppenheimer Molecular Dynamics

NASA Astrophysics Data System (ADS)

Perriot, Romain; Kober, Ed; Mniszewski, Sue; Martinez, Enrique; Niklasson, Anders; Yang, Ping; McGrane, Shawn; Cawkwell, Marc

2017-06-01

Characterizing the complex, rapid reactions of energetic materials under conditions of high temperatures and pressures presents strong experimental and computational challenges. The recently developed extended Lagrangian Born-Oppenheimer molecular dynamics formalism enables the long-term conservation of the total energy in microcanonical trajectories, and using a density functional tight binding formulation provides good chemical accuracy. We use this combined approach to study the evolution of temperature, pressure, and chemical species in shock-compressed liquid nitromethane over hundreds of picoseconds. The chemical species seen in nitromethane under shock compression are compared with those seen under static high temperature conditions. A reduced-order representation of the complex sequence of chemical reactions that characterize this system has been developed from the molecular dynamics simulations by focusing on classes of chemical reactions rather than specific molecular species. Time-resolved infra-red vibrational spectra were also computed from the molecular trajectories and compared to the chemical analysis. These spectra provide a time history of the species present in the system that can be compared directly with recent experiments at LANL.

Bottom-up, Robust Graphene Ribbon Electronics in All-Carbon Molecular Junctions.

PubMed

Supur, Mustafa; Van Dyck, Colin; Bergren, Adam J; McCreery, Richard L

2018-02-21

Large-area molecular electronic junctions consisting of 5-carbon wide graphene ribbons (GR) with lengths of 2-12 nm between carbon electrodes were fabricated by electrochemical reduction of diazotized 1,8-diaminonaphthalene. Their conductance greatly exceeds that observed for other molecular junctions of similar thicknesses, by a factor of >1 × 10 4 compared to polyphenylenes and >1 × 10 7 compared to alkane chains. The remarkable increase of conductance of the GR nanolayer results from (i) uninterrupted planarity of fused-arene structure affording extensive π-electron delocalization and (ii) enhanced electronic coupling of molecular layer with the carbon bottom contact by two-point covalent bonding, in agreement with DFT-based simulations.

Molecular Dynamics Analysis of Lysozyme Protein in Ethanol- Water Mixed Solvent

DTIC Science & Technology

2012-01-01

molecular dynamics simulations of solvent effect on lysozyme protein, using water, ethanol, and different concentrations of water-ethanol mixtures as...understood. This work focuses on detailed molecular dynamics simulations of solvent effect on lysozyme protein, using water, ethanol, and different...using GROMACS molecular dynamics simulation (MD) code. Compared to water environment, the lysozyme structure showed remarkable changes in water

Development and assessment of molecular diagnostic tests for 15 enteropathogens causing childhood diarrhoea: a multicentre study.

PubMed

Liu, Jie; Kabir, Furqan; Manneh, Jainaba; Lertsethtakarn, Paphavee; Begum, Sharmin; Gratz, Jean; Becker, Steve M; Operario, Darwin J; Taniuchi, Mami; Janaki, Lalitha; Platts-Mills, James A; Haverstick, Doris M; Kabir, Mamun; Sobuz, Shihab U; Nakjarung, Kaewkanya; Sakpaisal, Pimmada; Silapong, Sasikorn; Bodhidatta, Ladaporn; Qureshi, Shahida; Kalam, Adil; Saidi, Queen; Swai, Ndealilia; Mujaga, Buliga; Maro, Athanasia; Kwambana, Brenda; Dione, Michel; Antonio, Martin; Kibiki, Gibson; Mason, Carl J; Haque, Rashidul; Iqbal, Najeeha; Zaidi, Anita K M; Houpt, Eric R

2014-08-01

Childhood diarrhoea can be caused by many pathogens that are difficult to assay in the laboratory. Molecular diagnostic techniques provide a uniform method to detect and quantify candidate enteropathogens. We aimed to develop and assess molecular tests for identification of enteropathogens and their association with disease. We developed and assessed molecular diagnostic tests for 15 enteropathogens across three platforms-PCR-Luminex, multiplex real-time PCR, and TaqMan array card-at five laboratories worldwide. We judged the analytical and clinical performance of these molecular techniques against comparator methods (bacterial culture, ELISA, and PCR) using 867 diarrhoeal and 619 non-diarrhoeal stool specimens. We also measured molecular quantities of pathogens to predict the association with diarrhoea, by univariate logistic regression analysis. The molecular tests showed very good analytical and clinical performance at all five laboratories. Comparator methods had limited sensitivity compared with the molecular techniques (20-85% depending on the target) but good specificity (median 97·3%, IQR 96·5-98·9; mean 95·2%, SD 9·1). Positive samples by comparator methods usually had higher molecular quantities of pathogens than did negative samples, across almost all platforms and for most pathogens (p<0·05). The odds ratio for diarrhoea at a given quantity (measured by quantification cycle, Cq) showed that for most pathogens associated with diarrhoea-including Campylobacter jejuni and Campylobacter coli, Cryptosporidium spp, enteropathogenic Escherichia coli, heat-stable enterotoxigenic E coli, rotavirus, Shigella spp and enteroinvasive E coli, and Vibrio cholerae-the strength of association with diarrhoea increased at higher pathogen loads. For example, Shigella spp at a Cq range of 15-20 had an odds ratio of 8·0 (p<0·0001), but at a Cq range of 25-30 the odds ratio fell to 1·7 (p=0·043). Molecular diagnostic tests can be implemented successfully and with fidelity across laboratories around the world. In the case of diarrhoea, these techniques can detect pathogens with high sensitivity and ascribe diarrhoeal associations based on quantification, including in mixed infections, providing rich and unprecedented measurements of infectious causes. Bill & Melinda Gates Foundation Next Generation Molecular Diagnostics Project. Copyright © 2014 Elsevier Ltd. All rights reserved.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics.

PubMed

Armen, Roger S; Chen, Jianhan; Brooks, Charles L

2009-10-13

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and "noise" that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds.

An Evaluation of Explicit Receptor Flexibility in Molecular Docking Using Molecular Dynamics and Torsion Angle Molecular Dynamics

PubMed Central

Armen, Roger S.; Chen, Jianhan; Brooks, Charles L.

2009-01-01

Incorporating receptor flexibility into molecular docking should improve results for flexible proteins. However, the incorporation of explicit all-atom flexibility with molecular dynamics for the entire protein chain may also introduce significant error and “noise” that could decrease docking accuracy and deteriorate the ability of a scoring function to rank native-like poses. We address this apparent paradox by comparing the success of several flexible receptor models in cross-docking and multiple receptor ensemble docking for p38α mitogen-activated protein (MAP) kinase. Explicit all-atom receptor flexibility has been incorporated into a CHARMM-based molecular docking method (CDOCKER) using both molecular dynamics (MD) and torsion angle molecular dynamics (TAMD) for the refinement of predicted protein-ligand binding geometries. These flexible receptor models have been evaluated, and the accuracy and efficiency of TAMD sampling is directly compared to MD sampling. Several flexible receptor models are compared, encompassing flexible side chains, flexible loops, multiple flexible backbone segments, and treatment of the entire chain as flexible. We find that although including side chain and some backbone flexibility is required for improved docking accuracy as expected, docking accuracy also diminishes as additional and unnecessary receptor flexibility is included into the conformational search space. Ensemble docking results demonstrate that including protein flexibility leads to to improved agreement with binding data for 227 active compounds. This comparison also demonstrates that a flexible receptor model enriches high affinity compound identification without significantly increasing the number of false positives from low affinity compounds. PMID:20160879

Correlation and agreement between eplet mismatches calculated using serological, low-intermediate and high resolution molecular human leukocyte antigen typing methods

PubMed Central

Fidler, Samantha; D’Orsogna, Lloyd; Irish, Ashley B.; Lewis, Joshua R.; Wong, Germaine; Lim, Wai H.

2018-01-01

Structural human leukocyte antigen (HLA) matching at the eplet level can be identified by HLAMatchmaker, which requires the entry of four-digit alleles. The aim of this study was to evaluate the agreement between eplet mismatches calculated by serological and two-digit typing methods compared to high-resolution four-digit typing. In a cohort of 264 donor/recipient pairs, the evaluation of measurement error was assessed using intra-class correlation to confirm the absolute agreement between the number of eplet mismatches at class I (HLA-A, -B, C) and II loci (HLA-DQ and -DR) calculated using serological or two-digit molecular typing compared to four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches between the HLA typing methods was also determined. Intra-class correlation coefficients between serological and four-digit molecular typing methods were 0.969 (95% confidence intervals [95% CI] 0.960–0.975) and 0.926 (95% CI 0.899–0.944), respectively; and 0.995 (95% CI 0.994–0.996) and 0.993 (95% CI 0.991–0.995), respectively between two-digit and four-digit molecular typing methods. The proportion of donor/recipient pairs with a difference of >5 eplet mismatches at class I and II loci was 4% and 16% for serological versus four-digit molecular typing methods, and 0% and 2% for two-digit versus four-digit molecular typing methods, respectively. In this small predominantly Caucasian population, compared with serology, there is a high level of agreement in the number of eplet mismatches calculated using two-compared to four-digit molecular HLA-typing methods, suggesting that two-digit typing may be sufficient in determining eplet mismatch load in kidney transplantation. PMID:29568344

Variable expression of molecular markers in juvenile nasopharyngeal angiofibroma.

PubMed

Mishra, A; Pandey, A; Mishra, S C

2017-09-01

Molecular categorisation may explain the wide variation in the clinical characteristics of juvenile nasopharyngeal angiofibroma. Variations in molecular markers in juvenile nasopharyngeal angiofibroma in an Indian population were investigated and compared with global reports. Variable molecular marker expression was demonstrated at the regional and global levels. A wide variation in molecular characteristics is evident. Molecular data have been reported for only 11 countries, indicating a clear geographical bias. Only 58 markers have been studied, and most are yet to be validated. Research into the molecular epidemiology of juvenile nasopharyngeal angiofibroma is still in its infancy. Although the molecular variation is not well understood, data obtained so far have prompted important research questions. Hence, multicentre collaborative molecular studies are needed to establish the aetiopathogenesis and establish molecular surrogates for clinical characteristics.

The Effects of Water Matrix on Decay of Human Fecal Molecular Markers and Campylobacter spp.

EPA Science Inventory

Although molecular source tracking for human fecal contamination is used on a wide range of sample types, little is known about comparative decay of proposed molecular markers under different conditions, or correlation with pathogen decay. Our purpose was to measure correlations ...

Vulvar and vaginal melanoma: A unique subclass of mucosal melanoma based on a comprehensive molecular analysis of 51 cases compared with 2253 cases of nongynecologic melanoma.

PubMed

Hou, June Y; Baptiste, Caitlin; Hombalegowda, Radhika Bangalore; Tergas, Ana I; Feldman, Rebecca; Jones, Nathaniel L; Chatterjee-Paer, Sudeshna; Bus-Kwolfski, Ama; Wright, Jason D; Burke, William M

2017-04-15

Optimal treatments for vulvar and vaginal melanomas (VVMs) have not been identified. Herein, the authors compare molecular profiles between VVM and nongynecologic melanoma (NGM) subtypes with the objective of identifying novel, targetable biomarkers. In total, 2304 samples of malignant melanoma that were submitted to Caris Life Sciences between 2009 and 2015 were reviewed. In situ hybridization and immunohistochemistry were used to assess copy numbers and protein expression of selected genes. Sequenced variants were analyzed using a proprietary cancer panel. In total, 51 VVMs (14 vaginal and 37 vulvar melanomas) were compared with 2253 malignant NGMs, including 2127 cutaneous, 105 mucosal, and 21 acral melanomas. In VVMs, B-Raf proto-oncogene serine/threonine kinase (BRAF) was the most frequently mutated gene (26%) compared with 8.3% of mucosal NGMs (P = .008). In BRAF-mutated tumors, fewer VVMs (50%), compared with NGMs (82.1%), had a variant within the valine codon 600 (V600) domain. The KIT mutation rate was highest in VVMs (22%) compared with 3% in cutaneous (P < .001) and 8.8% in mucosal (P = .05) melanoma subtypes. NRAS mutations were rare in VVMs compared with cutaneous (25.9%; P = .009) and acral (40.6%; P = .002) melanoma subtypes. PD-L1 (56%) and PD-1 (75%) were frequently expressed in VVM, whereas PI3KCA pathway mutations and estrogen receptor/progesterone receptor expression were rare. Compared with VVMs that had KIT mutations, wild-type KIT VVMs were more likely to express molecular markers suggestive of platinum resistance (ERCC1), alkylating sensitivity (MGMT), and anthracycline sensitivity (TOP2A). The unique molecular features of VVM render this disease a distinct subtype of melanoma. Gene-based molecular therapy and immunotherapies may be promising and should be evaluated in clinical trials. Cancer 2017;123:1333-1344. © 2016 American Cancer Society. © 2016 American Cancer Society.

Simulation of size-exclusion chromatography distribution coefficients of comb-shaped molecules in spherical pores comparison of simulation and experiment.

PubMed

Radke, Wolfgang

2004-03-05

Simulations of the distribution coefficients of linear polymers and regular combs with various spacings between the arms have been performed. The distribution coefficients were plotted as a function of the number of segments in order to compare the size exclusion chromatography (SEC)-elution behavior of combs relative to linear molecules. By comparing the simulated SEC-calibration curves it is possible to predict the elution behavior of comb-shaped polymers relative to linear ones. In order to compare the results obtained by computer simulations with experimental data, a variety of comb-shaped polymers varying in side chain length, spacing between the side chains and molecular weights of the backbone were analyzed by SEC with light-scattering detection. It was found that the computer simulations could predict the molecular weights of linear molecules having the same retention volume with an accuracy of about 10%, i.e. the error in the molecular weight obtained by calculating the molecular weight of the comb-polymer based on a calibration curve constructed using linear standards and the results of the computer simulations are of the same magnitude as the experimental error of absolute molecular weight determination.

Comparing the Ability of Enhanced Sampling Molecular Dynamics Methods To Reproduce the Behavior of Fluorescent Labels on Proteins.

PubMed

Walczewska-Szewc, Katarzyna; Deplazes, Evelyne; Corry, Ben

2015-07-14

Adequately sampling the large number of conformations accessible to proteins and other macromolecules is one of the central challenges in molecular dynamics (MD) simulations; this activity can be difficult, even for relatively simple systems. An example where this problem arises is in the simulation of dye-labeled proteins, which are now being widely used in the design and interpretation of Förster resonance energy transfer (FRET) experiments. In this study, MD simulations are used to characterize the motion of two commonly used FRET dyes attached to an immobilized chain of polyproline. Even in this simple system, the dyes exhibit complex behavior that is a mixture of fast and slow motions. Consequently, very long MD simulations are required to sufficiently sample the entire range of dye motion. Here, we compare the ability of enhanced sampling methods to reproduce the behavior of fluorescent labels on proteins. In particular, we compared Accelerated Molecular Dynamics (AMD), metadynamics, Replica Exchange Molecular Dynamics (REMD), and High Temperature Molecular Dynamics (HTMD) to equilibrium MD simulations. We find that, in our system, all of these methods improve the sampling of the dye motion, but the most significant improvement is achieved using REMD.

Evaluation of serological and molecular tests used to identify Toxoplasma gondii infection in pregnant women attended in a public health service in São Paulo state, Brazil.

PubMed

Murata, Fernando Henrique Antunes; Ferreira, Marina Neves; Pereira-Chioccola, Vera Lucia; Spegiorin, Lígia Cosentino Junqueira Franco; Meira-Strejevitch, Cristina da Silva; Gava, Ricardo; Silveira-Carvalho, Aparecida Perpétuo; de Mattos, Luiz Carlos; Brandão de Mattos, Cinara Cássia

2017-09-01

Toxoplasmosis during pregnancy can have severe consequences. The use of sensitive and specific serological and molecular methods is extremely important for the correct diagnosis of the disease. We compared the ELISA and ELFA serological methods, conventional PCR (cPCR), Nested PCR and quantitative PCR (qPCR) in the diagnosis of Toxoplasma gondii infection in pregnant women without clinical suspicion of toxoplasmosis (G1=94) and with clinical suspicion of toxoplasmosis (G2=53). The results were compared using the Kappa index, and the sensitivity, specificity, positive predictive value and negative predictive value were calculated. The results of the serological methods showed concordance between the ELISA and ELFA methods even though ELFA identified more positive cases than ELISA. Molecular methods were discrepant with cPCR using B22/23 primers having greater sensitivity and lower specificity compared to the other molecular methods. Copyright © 2017 Elsevier Inc. All rights reserved.

The effect of water plasticization on the molecular mobility and crystallization tendency of amorphous disaccharides.

PubMed

Heljo, Ville Petteri; Nordberg, Antti; Tenho, Mikko; Virtanen, Tommi; Jouppila, Kirsi; Salonen, Jarno; Maunu, Sirkka Liisa; Juppo, Anne Mari

2012-10-01

To study how water plasticization affects the molecular mobility and crystallization tendency of freeze-dried trehalose, sucrose, melibiose and cellobiose. Freeze-dried disaccharides were subjected to different relative humidity atmospheres and their physical stabilities were evaluated. Lyophilizate water sorption tendencies and glass transition temperatures were modeled using Brunauer-Emmett-Teller (BET) and Gordon-Taylor (GT) equations, respectively. Sucrose and cellobiose crystallization tendencies were compared by using the concept of reduced crystallization temperature (RCT), and the molecular mobilities of trehalose and melibiose were compared by measuring their T(1)H relaxation time constants. Based on the BET and GT models, water sorption tendency and the resulting plasticizing effect were different in sucrose when compared to the other disaccharides. Trehalose and melibiose exhibited generally slower crystallization rates when compared to sucrose and cellobiose. Amorphous melibiose was shown to be particularly stable within the studied water content range, which may have partly been caused by its relatively slow molecular mobility. Slow amorphous-to-crystalline transition rate is known to be important for lyoprotecting excipients when formulating a robust drug product. The physical stabilities of amorphous trehalose and melibiose even with relatively high water contents might make their use advantageous in this respect compared to sucrose and cellobiose.

Avoiding pitfalls in molecular genetic testing: case studies of high-resolution array comparative genomic hybridization testing in the definitive diagnosis of Mowat-Wilson syndrome.

PubMed

Kluk, Michael Joseph; An, Yu; James, Philip; Coulter, David; Harris, David; Wu, Bai-Lin; Shen, Yiping

2011-05-01

The molecular testing options available for the diagnosis of genetic disorders are numerous and include a variety of different assay platforms. The consultative input of molecular pathologists and cytogeneticists, working closely with the ordering clinicians, is often important for definitive diagnosis. Herein, we describe two patients who had long histories of unexplained signs and symptoms with a high clinical suspicion of an underlying genetic etiology. Initial molecular testing in both cases was negative, but the application of high-resolution array comparative genomic hybridization technology lead to definitive diagnosis in both cases. We summarize the clinical findings and molecular testing in each case, discuss the differential diagnoses, and review the clinical and pathological findings of Mowat-Wilson syndrome. This report highlights the importance for those involved in molecular testing to know the nature of the underlying genetic abnormalities associated with the suspected diagnosis, to recognize the limitations of each testing platform, and to persistently pursue repeat testing using high-resolution technologies when indicated. This concept is applicable to both germline and somatic molecular genetic testing. Copyright © 2011 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.

Masses, luminosities and dynamics of galactic molecular clouds

NASA Technical Reports Server (NTRS)

Solomon, P. M.; Rivolo, A. R.; Mooney, T. J.; Barrett, J. W.; Sage, L. J.

1987-01-01

Star formation in galaxies takes place in molecular clouds and the Milky Way is the only galaxy in which it is possible to resolve and study the physical properties and star formation activity of individual clouds. The masses, luminosities, dynamics, and distribution of molecular clouds, primarily giant molecular clouds in the Milky Way are described and analyzed. The observational data sets are the Massachusetts-Stony Brook CO Galactic Plane Survey and the IRAS far IR images. The molecular mass and infrared luminosities of glactic clouds are then compared with the molecular mass and infrared luminosities of external galaxies.

Gene-Transformation-Induced Changes in Chemical Functional Group Features and Molecular Structure Conformation in Alfalfa Plants Co-Expressing Lc-bHLH and C1-MYB Transcriptive Flavanoid Regulatory Genes: Effects of Single-Gene and Two-Gene Insertion.

PubMed

Heendeniya, Ravindra G; Yu, Peiqiang

2017-03-20

Alfalfa ( Medicago sativa L.) genotypes transformed with Lc-bHLH and Lc transcription genes were developed with the intention of stimulating proanthocyanidin synthesis in the aerial parts of the plant. To our knowledge, there are no studies on the effect of single-gene and two-gene transformation on chemical functional groups and molecular structure changes in these plants. The objective of this study was to use advanced molecular spectroscopy with multivariate chemometrics to determine chemical functional group intensity and molecular structure changes in alfalfa plants when co-expressing Lc-bHLH and C1-MYB transcriptive flavanoid regulatory genes in comparison with non-transgenic (NT) and AC Grazeland (ACGL) genotypes. The results showed that compared to NT genotype, the presence of double genes ( Lc and C1 ) increased ratios of both the area and peak height of protein structural Amide I/II and the height ratio of α-helix to β-sheet. In carbohydrate-related spectral analysis, the double gene-transformed alfalfa genotypes exhibited lower peak heights at 1370, 1240, 1153, and 1020 cm -1 compared to the NT genotype. Furthermore, the effect of double gene transformation on carbohydrate molecular structure was clearly revealed in the principal component analysis of the spectra. In conclusion, single or double transformation of Lc and C1 genes resulted in changing functional groups and molecular structure related to proteins and carbohydrates compared to the NT alfalfa genotype. The current study provided molecular structural information on the transgenic alfalfa plants and provided an insight into the impact of transgenes on protein and carbohydrate properties and their molecular structure's changes.

Molecular weight dependence of LB morphology of poly(n-hexyl isocyanate) (PHIC).

PubMed

Morioka, Takako; Shibata, Osamu; Kawaguchi, Masami

2010-12-07

The morphologies of Langmuir-Blodgett (LB) films of two fractionated poly(n-hexyl isocyanate) (PHIC) and those of their binary mixtures were observed by AFM, together with those of an unfractionated PHIC. The low molecular weight PHIC formed random packing of bundles consisting of rigid rods, while the high molecular weight PHIC formed random packing of bundles consisting of hairy rods. Bundle interpenetration was observed only for the latter in the semidilute regime. In the bilayer region, the area occupied by the PHIC bundles in the upper layer was obviously smaller for the high molecular weight PHIC than for the low molecular weight PHIC, suggesting that the bundles of high molecular weight PHIC more easily interpenetrate than those of low molecular weight PHIC. For the blended films composed of both low and high molecular weight PHICs, the characteristic morphologies of the respective PHIC samples were no longer present. Moreover, the morphologies of the blended films appeared to resemble each other at any molar fraction owing to the ideal miscibility of the low molecular weight and high molecular weight PHICs. The morphologies of the blended films were also similar to that of the unfractionated PHIC film in the dilute regime. In the semidilute regime, the blended films became rounded owing to an increase in bundles interpenetration between PHICs as compared to that in the dilute regime, whereas the morphology of unfractionated PHIC films remained unchanged as compared to that in the dilute regime.

Enhancement of mechanical properties of 3D printed hydroxyapatite by combined low and high molecular weight polycaprolactone sequential infiltration.

PubMed

Suwanprateeb, Jintamai; Thammarakcharoen, Faungchat; Hobang, Nattapat

2016-11-01

A new infiltration technique using a combination of low and high molecular weight polycaprolactone (PCL) in sequence was developed as a mean to improve the mechanical properties of three dimensional printed hydroxyapatite (HA). It was observed that using either high (M n ~80,000) or low (M n ~10,000) molecular weight infiltration could only increase the flexural modulus compared to non-infiltrated HA, but did not affect strength, strain at break and energy at break. In contrast, a combination of low and high molecular infiltration in sequence increased the flexural modulus, strength and energy at break compared to those of non-infiltrated HA or infiltrated by high or low molecular weight PCL alone. This overall enhancement was found to be attributed to the densification of low molecular weight PCL and the reinforcement of high molecular PCL concurrently. The combined low and high molecular weight infiltration in sequence also maintained high osteoblast proliferation and differentiation of the composites at the similar level of the HA. Densification was a dominant mechanism for the change in modulus with porosity and density of the infiltrated HA/PCL composites. However, both densification and the reinforcing performance of the infiltration phase were crucial for strength and toughening enhancement of the composites possibly by the defect healing and stress shielding mechanisms. The sequence of using low molecular weight infiltration and followed by high molecular infiltration was seen to provide the greatest flexural properties and highest cells proliferation and differentiation capabilities.

Treatment Algorithms Based on Tumor Molecular Profiling: The Essence of Precision Medicine Trials.

PubMed

Le Tourneau, Christophe; Kamal, Maud; Tsimberidou, Apostolia-Maria; Bedard, Philippe; Pierron, Gaëlle; Callens, Céline; Rouleau, Etienne; Vincent-Salomon, Anne; Servant, Nicolas; Alt, Marie; Rouzier, Roman; Paoletti, Xavier; Delattre, Olivier; Bièche, Ivan

2016-04-01

With the advent of high-throughput molecular technologies, several precision medicine (PM) studies are currently ongoing that include molecular screening programs and PM clinical trials. Molecular profiling programs establish the molecular profile of patients' tumors with the aim to guide therapy based on identified molecular alterations. The aim of prospective PM clinical trials is to assess the clinical utility of tumor molecular profiling and to determine whether treatment selection based on molecular alterations produces superior outcomes compared with unselected treatment. These trials use treatment algorithms to assign patients to specific targeted therapies based on tumor molecular alterations. These algorithms should be governed by fixed rules to ensure standardization and reproducibility. Here, we summarize key molecular, biological, and technical criteria that, in our view, should be addressed when establishing treatment algorithms based on tumor molecular profiling for PM trials. © The Author 2015. Published by Oxford University Press.

A Comparative Study of Successful Central Nervous System Drugs Using Molecular Modeling

ERIC Educational Resources Information Center

Kim, Hyosub; Sulaimon, Segun; Menezes, Sandra; Son, Anne; Menezes, Warren J. C.

2011-01-01

Molecular modeling is a powerful tool used for three-dimensional visualization and for exploring electrostatic forces involved in drug transport. This tool enhances student understanding of structure-property relationships, as well as actively engaging them in class. Molecular modeling of several central nervous system (CNS) drugs is used to…

Using a Computer Animation to Teach High School Molecular Biology

ERIC Educational Resources Information Center

Rotbain, Yosi; Marbach-Ad, Gili; Stavy, Ruth

2008-01-01

We present an active way to use a computer animation in secondary molecular genetics class. For this purpose we developed an activity booklet that helps students to work interactively with a computer animation which deals with abstract concepts and processes in molecular biology. The achievements of the experimental group were compared with those…

MIMO: an efficient tool for molecular interaction maps overlap

PubMed Central

2013-01-01

Background Molecular pathways represent an ensemble of interactions occurring among molecules within the cell and between cells. The identification of similarities between molecular pathways across organisms and functions has a critical role in understanding complex biological processes. For the inference of such novel information, the comparison of molecular pathways requires to account for imperfect matches (flexibility) and to efficiently handle complex network topologies. To date, these characteristics are only partially available in tools designed to compare molecular interaction maps. Results Our approach MIMO (Molecular Interaction Maps Overlap) addresses the first problem by allowing the introduction of gaps and mismatches between query and template pathways and permits -when necessary- supervised queries incorporating a priori biological information. It then addresses the second issue by relying directly on the rich graph topology described in the Systems Biology Markup Language (SBML) standard, and uses multidigraphs to efficiently handle multiple queries on biological graph databases. The algorithm has been here successfully used to highlight the contact point between various human pathways in the Reactome database. Conclusions MIMO offers a flexible and efficient graph-matching tool for comparing complex biological pathways. PMID:23672344

Selective IR multiphoton dissociation of molecules in a pulsed gas-dynamically cooled molecular flow interacting with a solid surface as an alternative to low-energy methods of molecular laser isotope separation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makarov, G N; Petin, A N

2016-03-31

We report the results of studies on the isotope-selective infrared multiphoton dissociation (IR MFD) of SF{sub 6} and CF{sub 3}I molecules in a pulsed, gas-dynamically cooled molecular flow interacting with a solid surface. The productivity of this method in the conditions of a specific experiment (by the example of SF{sub 6} molecules) is evaluated. A number of low-energy methods of molecular laser isotope separation based on the use of infrared lasers for selective excitation of molecules are analysed and their productivity is estimated. The methods are compared with those of selective dissociation of molecules in the flow interacting with amore » surface. The advantages of this method compared to the low-energy methods of molecular laser isotope separation and the IR MPD method in the unperturbed jets and flows are shown. It is concluded that this method could be a promising alternative to the low-energy methods of molecular laser isotope separation. (laser separation of isotopes)« less

Molecular design of anticancer drug leads based on three-dimensional quantitative structure-activity relationship.

PubMed

Huang, Xiao Yan; Shan, Zhi Jie; Zhai, Hong Lin; Li, Li Na; Zhang, Xiao Yun

2011-08-22

Heat shock protein 90 (Hsp90) takes part in the developments of several cancers. Novobiocin, a typically C-terminal inhibitor for Hsp90, will probably used as an important anticancer drug in the future. In this work, we explored the valuable information and designed new novobiocin derivatives based on a three-dimensional quantitative structure-activity relationship (3D QSAR). The comparative molecular field analysis and comparative molecular similarity indices analysis models with high predictive capability were established, and their reliabilities are supported by the statistical parameters. Based on the several important influence factors obtained from these models, six new novobiocin derivatives with higher inhibitory activities were designed and confirmed by the molecular simulation with our models, which provide the potential anticancer drug leads for further research.

Morphological and molecular data for larval stages of four species of Petasiger Dietz, 1909 (Digenea: Echinostomatidae) with an updated key to the known cercariae from the Palaearctic.

PubMed

Selbach, Christian; Soldánová, Miroslava; Georgieva, Simona; Kostadinova, Aneta; Kalbe, Martin; Sures, Bernd

2014-10-01

Large-tailed echinostomatid cercariae of the genus Petasiger Dietz, 1909 (Digenea: Echinostomatidae) from the planorbid snails Gyraulus albus (Müller) and Planorbis planorbis (L.) collected in Germany and the Czech Republic and metacercariae from Gasterosteus aculeatus L. (Gasterosteiformes: Gasterosteidae) collected in Canada are characterised morphologically and molecularly. The rediae, cercariae and metacercariae are described in detail and compared with the existing data on the larval stages of Petasiger spp. Comparative molecular analyses using 28S rDNA and nad1 mitochondrial sequences supported the distinct status of four species of Petasiger. Molecular and morphological evidence for their distinction and an updated key to the known large-tailed cercariae of Petasiger from the Palaearctic are provided.

Fractionation of Organosolv Lignin Using Acetone:Water and Properties of the Obtained Fractions

DOE PAGES

Sadeghifar, Hasan; Wells, Tyrone; Le, Rosemary Khuu; ...

2016-11-07

In this study, lignin fractions with different molecular weight were prepared using a simple and almost green method from switchgrass and pine organosolv lignin. Different proportions of acetone in water, ranging from 30 to 60%, were used for lignin fractionation. A higher concentration of acetone dissolved higher molecular weight fractions of the lignin. Fractionated organosolv lignin showed different molecular weight and functional groups. Higher molecular weight fractions exhibited more aliphatic and less phenolic OH than lower molecular weight fractions. Lower molecular weight fractions lead to more homogeneous structure compared to samples with a higher molecular weight. In conclusion, all fractionsmore » showed strong antioxidant activity.« less

Molecular dynamics simulation and NMR investigation of the association of the β-blockers atenolol and propranolol with a chiral molecular micelle

NASA Astrophysics Data System (ADS)

Morris, Kevin F.; Billiot, Eugene J.; Billiot, Fereshteh H.; Hoffman, Charlene B.; Gladis, Ashley A.; Lipkowitz, Kenny B.; Southerland, William M.; Fang, Yayin

2015-08-01

Molecular dynamics simulations and NMR spectroscopy were used to compare the binding of two β-blocker drugs to the chiral molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The molecular micelle is used as a chiral selector in capillary electrophoresis. This study is part of a larger effort to understand the mechanism of chiral recognition in capillary electrophoresis by characterizing the molecular micelle binding of chiral compounds with different geometries and charges. Propranolol and atenolol were chosen because their structures are similar, but their chiral interactions with the molecular micelle are different. Molecular dynamics simulations showed both propranolol enantiomers inserted their aromatic rings into the molecular micelle core and that (S)-propranolol associated more strongly with the molecular micelle than (R)-propranolol. This difference was attributed to stronger molecular micelle hydrogen bonding interactions experienced by (S)-propranolol. Atenolol enantiomers were found to bind near the molecular micelle surface and to have similar molecular micelle binding free energies.

Direct-Conversion Molecular Breast Imaging of Invasive Breast Cancer: Imaging Features, Extent of Invasive Disease, and Comparison Between Invasive Ductal and Lobular Histology.

PubMed

Conners, Amy Lynn; Jones, Katie N; Hruska, Carrie B; Geske, Jennifer R; Boughey, Judy C; Rhodes, Deborah J

2015-09-01

The purposes of this study were to compare the tumor appearance of invasive breast cancer on direct-conversion molecular breast imaging using a standardized lexicon and to determine how often direct-conversion molecular breast imaging identifies all known invasive tumor foci in the breast, and whether this differs for invasive ductal versus lobular histologic profiles. Patients with prior invasive breast cancer and concurrent direct-conversion molecular breast imaging examinations were retrospectively reviewed. Blinded review of direct-conversion molecular breast imaging examinations was performed by one of two radiologists, according to a validated lexicon. Direct-conversion molecular breast imaging findings were matched with lesions described on the pathology report to exclude benign reasons for direct-conversion molecular breast imaging findings and to document direct-conversion molecular breast imaging-occult tumor foci. Associations between direct-conversion molecular breast imaging findings and tumor histologic profiles were examined using chi-square tests. In 286 patients, 390 invasive tumor foci were present in 294 breasts. A corresponding direct-conversion molecular breast imaging finding was present for 341 of 390 (87%) tumor foci described on the pathology report. Invasive ductal carcinoma (IDC) tumor foci were more likely to be a mass (40% IDC vs 15% invasive lobular carcinoma [ILC]; p < 0.001) and to have marked intensity than were ILC foci (63% IDC vs 32% ILC; p < 0.001). Direct-conversion molecular breast imaging correctly revealed all pathology-proven foci of invasive disease in 79.8% of cases and was more likely to do so for IDC than for ILC (86.1% vs 56.7%; p < 0.0001). Overall, direct-conversion molecular breast imaging showed all known invasive foci in 249 of 286 (87%) patients. Direct-conversion molecular breast imaging features of invasive cancer, including lesion type and intensity, differ by histologic subtype. Direct-conversion molecular breast imaging is less likely to show all foci of ILC compared with IDC.

Primitive chain network simulations for entangled DNA solutions

NASA Astrophysics Data System (ADS)

Masubuchi, Yuichi; Furuichi, Kenji; Horio, Kazushi; Uneyama, Takashi; Watanabe, Hiroshi; Ianniruberto, Giovanni; Greco, Francesco; Marrucci, Giuseppe

2009-09-01

Molecular theories for polymer rheology are based on conformational dynamics of the polymeric chain. Hence, measurements directly related to molecular conformations appear more appealing than indirect ones obtained from rheology. In this study, primitive chain network simulations are compared to experimental data of entangled DNA solutions [Teixeira et al., Macromolecules 40, 2461 (2007)]. In addition to rheological comparisons of both linear and nonlinear viscoelasticities, a molecular extension measure obtained by Teixeira et al. through fluorescent microscopy is compared to simulations, in terms of both averages and distributions. The influence of flow on conformational distributions has never been simulated for the case of entangled polymers, and how DNA molecular individualism extends to the entangled regime is not known. The linear viscoelastic response and the viscosity growth curve in the nonlinear regime are found in good agreement with data for various DNA concentrations. Conversely, the molecular extension measure shows significant departures, even under equilibrium conditions. The reason for such discrepancies remains unknown.

Electron transport in dipyridazine and dipyridimine molecular junctions: a first-principles investigation

NASA Astrophysics Data System (ADS)

Parashar, Sweta

2018-05-01

We present density functional theory-nonequilibrium Green’s function method for electron transport of dipyridazine and dipyridimine molecular junctions with gold, copper and nickel electrodes. Our investigation reveals that the junctions formed with gold and copper electrodes bridging dipyridazine molecule through thiol anchoring group enhance current as compared to the junctions in which the molecule and electrode were coupled directly. Further, nickel electrode displays weak decrease of current with increase of voltage at about 1.2 V. The result is fully rationalized by means of the distribution of molecular orbitals as well as shift in molecular energy levels and HOMO-LUMO gap with applied bias voltage. Our findings are compared with theoretical and experimental results available for other molecular junctions. Present results predict potential avenues for changing the transport behavior by not only changing the electrodes, but also the position of nitrogen atom and type of anchoring-atom that connect molecule and electrodes, thus extending applications of dipyridazine and dipyridimine molecule in future integrated circuits.

Molecular continua for polymeric liquids in large-amplitude oscillatory shear flow

NASA Astrophysics Data System (ADS)

Giacomin, A. Jeffrey; Saengow, Chaimongkol

2018-05-01

In this paper, we connect a molecular description of the rheology of a polymeric liquid to a continuum description, and then test this connection for large-amplitude oscillatory shear (LAOS) flow. Specifically, for the continuum description, we use the 6-constant Oldroyd framework, and for the molecular, we use the simplest relevant molecular model, the suspension of rigid dumbbells. By relevant, we mean predicting at least higher harmonics in the shear stress response in LAOS. We call this connection a molecular continuum, and we examine two ways of arriving at this connection. The first goes through the retarded motion expansion, and the second expands each of a set of specific material functions (complex, steady shear, and steady uniaxial extensional viscosities). Both ways involve in comparing the coefficients of expansions and then solve for the six constants of the continuum framework in terms of the two constants of the rigid dumbbell suspension. The purpose of a molecular continuum is that many well-known results for rigid dumbbell suspensions in other flow fields can also be easily obtained, without having to firstly find the orientation distribution function. In this paper, we focus on the recent result for the rigid dumbbell suspension in LAOS. We compare the accuracies of the retarded motion molecular continuum (RMMC) with the material function molecular continuum (MFMC). We find the RMMC to be the most accurate for LAOS.

Molecular hydrodynamics: Vortex formation and sound wave propagation

DOE PAGES

Han, Kyeong Hwan; Kim, Changho; Talkner, Peter; ...

2018-01-14

In the present study, quantitative feasibility tests of the hydrodynamic description of a two-dimensional fluid at the molecular level are performed, both with respect to length and time scales. Using high-resolution fluid velocity data obtained from extensive molecular dynamics simulations, we computed the transverse and longitudinal components of the velocity field by the Helmholtz decomposition and compared them with those obtained from the linearized Navier-Stokes (LNS) equations with time-dependent transport coefficients. By investigating the vortex dynamics and the sound wave propagation in terms of these field components, we confirm the validity of the LNS description for times comparable to ormore » larger than several mean collision times. The LNS description still reproduces the transverse velocity field accurately at smaller times, but it fails to predict characteristic patterns of molecular origin visible in the longitudinal velocity field. Based on these observations, we validate the main assumptions of the mode-coupling approach. The assumption that the velocity autocorrelation function can be expressed in terms of the fluid velocity field and the tagged particle distribution is found to be remarkably accurate even for times comparable to or smaller than the mean collision time. This suggests that the hydrodynamic-mode description remains valid down to the molecular scale.« less

Molecular hydrodynamics: Vortex formation and sound wave propagation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han, Kyeong Hwan; Kim, Changho; Talkner, Peter

In the present study, quantitative feasibility tests of the hydrodynamic description of a two-dimensional fluid at the molecular level are performed, both with respect to length and time scales. Using high-resolution fluid velocity data obtained from extensive molecular dynamics simulations, we computed the transverse and longitudinal components of the velocity field by the Helmholtz decomposition and compared them with those obtained from the linearized Navier-Stokes (LNS) equations with time-dependent transport coefficients. By investigating the vortex dynamics and the sound wave propagation in terms of these field components, we confirm the validity of the LNS description for times comparable to ormore » larger than several mean collision times. The LNS description still reproduces the transverse velocity field accurately at smaller times, but it fails to predict characteristic patterns of molecular origin visible in the longitudinal velocity field. Based on these observations, we validate the main assumptions of the mode-coupling approach. The assumption that the velocity autocorrelation function can be expressed in terms of the fluid velocity field and the tagged particle distribution is found to be remarkably accurate even for times comparable to or smaller than the mean collision time. This suggests that the hydrodynamic-mode description remains valid down to the molecular scale.« less

Structural insights of Staphylococcus aureus FtsZ inhibitors through molecular docking, 3D-QSAR and molecular dynamics simulations.

PubMed

Ballu, Srilata; Itteboina, Ramesh; Sivan, Sree Kanth; Manga, Vijjulatha

2018-02-01

Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r 2 ncv and r 2 loo values. The predictive ability of these models was determined and an acceptable predictive correlation (r 2 Pred ) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors.

Structure-activity relationships of pyrethroid insecticides. Part 2. The use of molecular dynamics for conformation searching and average parameter calculation

NASA Astrophysics Data System (ADS)

Hudson, Brian D.; George, Ashley R.; Ford, Martyn G.; Livingstone, David J.

1992-04-01

Molecular dynamics simulations have been performed on a number of conformationally flexible pyrethroid insecticides. The results indicate that molecular dynamics is a suitable tool for conformational searching of small molecules given suitable simulation parameters. The structures derived from the simulations are compared with the static conformation used in a previous study. Various physicochemical parameters have been calculated for a set of conformations selected from the simulations using multivariate analysis. The averaged values of the parameters over the selected set (and the factors derived from them) are compared with the single conformation values used in the previous study.

American football and fatal exertional heat stroke: a case study of Korey Stringer.

PubMed

Grundstein, Andrew; Knox, John A; Vanos, Jennifer; Cooper, Earl R; Casa, Douglas J

2017-08-01

On August 1, 2001, Korey Stringer, a Pro Bowl offensive tackle for the Minnesota Vikings, became the first and to date the only professional American football player to die from exertional heat stroke (EHS). The death helped raise awareness of the dangers of exertional heat illnesses in athletes and prompted the development of heat safety policies at the professional, collegiate, and interscholastic levels. Despite the public awareness of this death, no published study has examined in detail the circumstances surrounding Stringer's fatal EHS. Using the well-documented details of the case, our study shows that Stringer's fatal EHS was the result of a combination of physiological limitations, organizational and treatment failings, and extreme environmental conditions. The COMfort FormulA (COMFA) energy budget model was used to assess the relative importance of several extrinsic factors on Stringer's EHS, including weather conditions, clothing insulation, and activity levels. We found that Stringer's high-intensity training in relation to the oppressive environmental conditions was the most prominent factor in producing dangerous, uncompensable heat stress conditions and that the full football uniform played a smaller role in influencing Stringer's energy budget. The extreme energy budget levels that led to the fatal EHS would have been avoided according to our modeling through a combination of reduced intensity and lower clothing insulation. Finally, a long delay in providing medical treatment made the EHS fatal. These results highlight the importance of modern heat safety guidelines that provide controls on extrinsic factors, such as the adjustment of duration and intensity of training along with protective equipment modifications based on environmental conditions and the presence of an emergency action plan focused on rapid recognition and immediate on-site aggressive cooling of EHS cases.

American football and fatal exertional heat stroke: a case study of Korey Stringer

NASA Astrophysics Data System (ADS)

Grundstein, Andrew; Knox, John A.; Vanos, Jennifer; Cooper, Earl R.; Casa, Douglas J.

2017-08-01

On August 1, 2001, Korey Stringer, a Pro Bowl offensive tackle for the Minnesota Vikings, became the first and to date the only professional American football player to die from exertional heat stroke (EHS). The death helped raise awareness of the dangers of exertional heat illnesses in athletes and prompted the development of heat safety policies at the professional, collegiate, and interscholastic levels. Despite the public awareness of this death, no published study has examined in detail the circumstances surrounding Stringer's fatal EHS. Using the well-documented details of the case, our study shows that Stringer's fatal EHS was the result of a combination of physiological limitations, organizational and treatment failings, and extreme environmental conditions. The COMfort FormulA (COMFA) energy budget model was used to assess the relative importance of several extrinsic factors on Stringer's EHS, including weather conditions, clothing insulation, and activity levels. We found that Stringer's high-intensity training in relation to the oppressive environmental conditions was the most prominent factor in producing dangerous, uncompensable heat stress conditions and that the full football uniform played a smaller role in influencing Stringer's energy budget. The extreme energy budget levels that led to the fatal EHS would have been avoided according to our modeling through a combination of reduced intensity and lower clothing insulation. Finally, a long delay in providing medical treatment made the EHS fatal. These results highlight the importance of modern heat safety guidelines that provide controls on extrinsic factors, such as the adjustment of duration and intensity of training along with protective equipment modifications based on environmental conditions and the presence of an emergency action plan focused on rapid recognition and immediate on-site aggressive cooling of EHS cases.

Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease.

PubMed

Ellingford, Jamie M; Barton, Stephanie; Bhaskar, Sanjeev; Williams, Simon G; Sergouniotis, Panagiotis I; O'Sullivan, James; Lamb, Janine A; Perveen, Rahat; Hall, Georgina; Newman, William G; Bishop, Paul N; Roberts, Stephen A; Leach, Rick; Tearle, Rick; Bayliss, Stuart; Ramsden, Simon C; Nemeth, Andrea H; Black, Graeme C M

2016-05-01

To compare the efficacy of whole genome sequencing (WGS) with targeted next-generation sequencing (NGS) in the diagnosis of inherited retinal disease (IRD). Case series. A total of 562 patients diagnosed with IRD. We performed a direct comparative analysis of current molecular diagnostics with WGS. We retrospectively reviewed the findings from a diagnostic NGS DNA test for 562 patients with IRD. A subset of 46 of 562 patients (encompassing potential clinical outcomes of diagnostic analysis) also underwent WGS, and we compared mutation detection rates and molecular diagnostic yields. In addition, we compared the sensitivity and specificity of the 2 techniques to identify known single nucleotide variants (SNVs) using 6 control samples with publically available genotype data. Diagnostic yield of genomic testing. Across known disease-causing genes, targeted NGS and WGS achieved similar levels of sensitivity and specificity for SNV detection. However, WGS also identified 14 clinically relevant genetic variants through WGS that had not been identified by NGS diagnostic testing for the 46 individuals with IRD. These variants included large deletions and variants in noncoding regions of the genome. Identification of these variants confirmed a molecular diagnosis of IRD for 11 of the 33 individuals referred for WGS who had not obtained a molecular diagnosis through targeted NGS testing. Weighted estimates, accounting for population structure, suggest that WGS methods could result in an overall 29% (95% confidence interval, 15-45) uplift in diagnostic yield. We show that WGS methods can detect disease-causing genetic variants missed by current NGS diagnostic methodologies for IRD and thereby demonstrate the clinical utility and additional value of WGS. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Exploring scarless healing of oral soft tissues.

PubMed

Larjava, Hannu; Wiebe, Colin; Gallant-Behm, Corrie; Hart, David A; Heino, Jyrki; Häkkinen, Lari

2011-01-01

Our research group is comparing clinical, histological and molecular healing profiles of oral and skin wounds using human and pig models. The goal is to determine the molecular cues that lead to scarless healing in the oral mucosa and use that information to develop scar prevention therapies for skin and prevent aberrant wound healing in the oral cavity. Wound healing in human and pig palatal mucosa is almost identical, and scar formation is reduced in oral wounds compared with skin. The striking difference between these tissues is transient and rapidly resolving inflammation in oral wounds compared with long-lasting inflammation in the skin wounds. Currently, we are looking at wound transcriptomes (genes differentially regulated) and proteomes (a set of proteins) to investigate how these wound healing responses in skin and oral mucosa are regulated at the molecular level.

How Molecular Structure Affects Mechanical Properties of an Advanced Polymer

NASA Technical Reports Server (NTRS)

Nicholson, Lee M.; Whitley, Karen S.; Gates, Thomas S.; Hinkley, Jeffrey A.

2000-01-01

density was performed over a range of temperatures below the glass transition temperature. The physical characterization, elastic properties and notched tensile strength all as a function of molecular weight and test temperature were determined. For the uncrosslinked SI material, it was shown that notched tensile strength is a strong function of both temperature and molecular weight, whereas stiffness is only a strong function of temperature. For the crosslinked PETI-SI material, it was shown that the effect of crosslinking significantly enhances the mechanical performance of the low molecular weight material; comparable to that exhibited by the high molecular weight material.

Investigation of Y/SBA Composite Molecular Sieves Morphology Control and Catalytic Performance for n-Pentane Aromatization

PubMed Central

Shi, Chun-Wei; Wu, Wen-Yuan; Li, Shuai; Bian, Xue; Zhao, Shan-lin; Pei, Ming-Yuan

2016-01-01

Using Y molecular sieve as the core, Y/SBA-15 composite molecular sieves were prepared by different crystallization methods in the paper. The growth process and morphologies of the composite molecular sieves were controlled by adjusting the synthesis factors. The structures and acidity of two kinds of composite molecular sieves were characterized by X-ray diffraction (XRD), N2 adsorption/desorption, transmission electron microscopy (TEM), and NH3-TPD. The catalysis performances of the composite molecular sieves were investigated in the aromatization reaction of n-pentane. The results indicated that the desired core-shell composite molecular sieves were obtained when the crystallization conditions were 36 hours, 100 °C and secondary crystallization. The aromatization results showed that core-shell composite molecular sieves had better selectivity for producing high application value xylenes compared to mixed-crystal composite molecular sieves. PMID:27029526

MOLECULAR MARKER ANALYSIS OF DEARS SAMPLES

EPA Science Inventory

Source apportionment based on organic molecular markers provides a promising approach for meeting the Detroit Exposure and Aerosol Research Study (DEARS) objective of comparing source contributions between community air monitoring stations and various neighborhoods. Source appor...

(ISEA) MOLECULAR MARKER ANALYSIS OF DEARS SAMPLES

EPA Science Inventory

Source apportionment based on organic molecular markers provides a promising approach for meeting the Detroit Exposure and Aerosol Research Study (DEARS) objective of comparing source contributions between community air monitoring stations and various neighborhoods. Source appor...

Comparative studies on molecular structure, vibrational spectra and hyperpolarizabilies of NLO chromophore Ethyl 4-Dimethylaminobenzoate

NASA Astrophysics Data System (ADS)

Amalanathan, M.; Jasmine, G. Femina; Roy, S. Dawn Dharma

2017-08-01

The molecular structure, vibrational spectra and polarizabilities of Ethyl 4-Dimethylaminobenzoate (EDAB) was investigated by density functional theory employing Becke's three parameter hybrid exchange functional with Lee-Yang-Parr (B3LYP) co-relational functional involving 6-311++G(d,p) basis set and compared with some other levels. A detailed interpretation of the IR and Raman spectra of EDBA have been reported and analyzed. Complete vibrational assignments of the vibrational modes have been done on the basis of the potential energy distribution (TED) using VEDA software. The molecular electrostatic potential mapped onto total density surface has been obtained. A study on the electronic properties, such as absorption wavelength, and frontier molecular orbitals energy, was performed using DFT approach. The stability of the molecule arising from hyper conjugative interactions and accompanying charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The natural and Mulliken charge also calculated and compared with different level of calculation. The dipole moment, polarizability and first, second order hyperpolarizabilities of the title molecule were calculated and compared with the experimental values. The energy gap between frontier orbitals has been used along with electric moments and first order hyperpolarizability, to understand the non linear optical (NLO) activity of the molecule. The NLO activity of molecule was confirmed by SHG analysis.

The Effect of Different Molecular Models on High School Students' Conceptions of Molecular Genetics

ERIC Educational Resources Information Center

Rotbain, Yosi; Stavy, Ruth; Marbach-Ad, Gili

2008-01-01

Our main goal in this study was to explore whether the use of models in high school molecular genetics instruction can contribute to students' understanding of concepts and processes in genetics. Three hundred and nineteen students from four comparable groups of 11th- and 12th-grade students participated. The control group (116 students) was…

The temperature of large dust grains in molecular clouds

NASA Technical Reports Server (NTRS)

Clark, F. O.; Laureijs, R. J.; Prusti, T.

1991-01-01

The temperature of the large dust grains is calculated from three molecular clouds ranging in visual extinction from 2.5 to 8 mag, by comparing maps of either extinction derived from star counts or gas column density derived from molecular observations to I(100). Both techniques show the dust temperature declining into clouds. The two techniques do not agree in absolute scale.

Effect of polyacrylamide on soil physical and hydraulic properties

NASA Astrophysics Data System (ADS)

Albalasmeh, Ammar; Gharaibeh, Mamoun; Hamdan, Enas

2017-04-01

The effect of polyacrylamide (PAM), as a soil conditioner, on selected soil physical and hydraulic properties (infiltration rate (f(t)), hydraulic conductivity (HC), soil moisture content, aggregate stability (AS), and soil aggregation) was studied. Two types of anionic PAM were used: Low molecular weight (LPAM) (1×105 g/mol) with medium charge density (33-43) and high molecular weight (HPAM) (1-6×106 g/mol) with medium charge density (33-43). Sandy loam soil was packed into plastic columns; PAM solutions at different concentrations (100, 250, 500, and 1000 mg L-1) were used every two weeks in four wetting and drying cycles. The highest infiltration rate value was 0.16 mm s-1 at 1000 mg/L low molecular weight PAM while the highest value of infiltration rate in high PAM molecular weight was 0.11 mm s-1 compared to the control (0.01 mm s-1). Soil HC was about 3.00 cm h-1 for LPAM at 1000 mg L-1 PAM, while the highest value for HPAM was about 2 cm h-1 for the same concentration, compared to the control. The amount of water that can be held by soil increased with the addition of PAM compared to the control. Differences in water content were more pronounced in LPAM compared to HPAM. The addition of LPAM increased aggregate stability proportional to PAM concentration. Moreover, 1000 mg L-1 produced the highest aggregate stability (19{%}) compared to HPAM and control (7{%} and 5{%}), respectively. As PAM concentration increased, the geometric mean diameter (GMD) increased for both PAM molecular weights compared to control (0.4 mm). At 1000 mg L-1 the GMD values were 0.88 mm and 0.79 mm for LPAM and HPAM, respectively. The addition of PAM improved soil physical and hydraulic properties, with an advantage to LPAM owing that to its ability to penetrate soil aggregates and therefore stabilizing them.

Study of Barley Grain Molecular Structure for Ruminants Using DRIFT, FTIR-ATR and Synchrotron Radiation Infrared Microspectroscopy (SR-IMS): A Review

NASA Astrophysics Data System (ADS)

Yu, Peiqiang

2012-05-01

Barley inherent structures are highly associated with nutrient utilization and availability in both humans and animals. Barley has different degradation kinetics compared with other cereal grains. It has a relatively higher degradation rate and extent, which often cause digestive disorder in the rumen. Therefore understanding barley inherent structure at cellular and molecular levels and processing-induced structure changes is important, because we can manipulate barley inherent structures and digestive behaviors. Several molecular spectroscopy techniques can be used to detect barley inherent structures at cellular and molecular levels. This article reviews several applications of the IR molecular spectral bioanalytical techniques - DRIFT, FT/IR-ATR and SR-IMS for barley chemistry, molecular structure and molecular nutrition research

Atomic scale friction of molecular adsorbates during diffusion.

PubMed

Lechner, B A J; de Wijn, A S; Hedgeland, H; Jardine, A P; Hinch, B J; Allison, W; Ellis, J

2013-05-21

Experimental observations suggest that molecular adsorbates exhibit a larger friction coefficient than atomic species of comparable mass, yet the origin of this increased friction is not well understood. We present a study of the microscopic origins of friction experienced by molecular adsorbates during surface diffusion. Helium spin-echo measurements of a range of five-membered aromatic molecules, cyclopentadienyl, pyrrole, and thiophene, on a copper(111) surface are compared with molecular dynamics simulations of the respective systems. The adsorbates have different chemical interactions with the surface and differ in bonding geometry, yet the measurements show that the friction is greater than 2 ps(-1) for all these molecules. We demonstrate that the internal and external degrees of freedom of these adsorbate species are a key factor in the underlying microscopic processes and identify the rotation modes as the ones contributing most to the total measured friction coefficient.

Direct mapping of electrical noise sources in molecular wire-based devices

PubMed Central

Cho, Duckhyung; Lee, Hyungwoo; Shekhar, Shashank; Yang, Myungjae; Park, Jae Yeol; Hong, Seunghun

2017-01-01

We report a noise mapping strategy for the reliable identification and analysis of noise sources in molecular wire junctions. Here, different molecular wires were patterned on a gold substrate, and the current-noise map on the pattern was measured and analyzed, enabling the quantitative study of noise sources in the patterned molecular wires. The frequency spectra of the noise from the molecular wire junctions exhibited characteristic 1/f2 behavior, which was used to identify the electrical signals from molecular wires. This method was applied to analyze the molecular junctions comprising various thiol molecules on a gold substrate, revealing that the noise in the junctions mainly came from the fluctuation of the thiol bonds. Furthermore, we quantitatively compared the frequencies of such bond fluctuations in different molecular wire junctions and identified molecular wires with lower electrical noise, which can provide critical information for designing low-noise molecular electronic devices. Our method provides valuable insights regarding noise phenomena in molecular wires and can be a powerful tool for the development of molecular electronic devices. PMID:28233821

Direct mapping of electrical noise sources in molecular wire-based devices

NASA Astrophysics Data System (ADS)

Cho, Duckhyung; Lee, Hyungwoo; Shekhar, Shashank; Yang, Myungjae; Park, Jae Yeol; Hong, Seunghun

2017-02-01

We report a noise mapping strategy for the reliable identification and analysis of noise sources in molecular wire junctions. Here, different molecular wires were patterned on a gold substrate, and the current-noise map on the pattern was measured and analyzed, enabling the quantitative study of noise sources in the patterned molecular wires. The frequency spectra of the noise from the molecular wire junctions exhibited characteristic 1/f2 behavior, which was used to identify the electrical signals from molecular wires. This method was applied to analyze the molecular junctions comprising various thiol molecules on a gold substrate, revealing that the noise in the junctions mainly came from the fluctuation of the thiol bonds. Furthermore, we quantitatively compared the frequencies of such bond fluctuations in different molecular wire junctions and identified molecular wires with lower electrical noise, which can provide critical information for designing low-noise molecular electronic devices. Our method provides valuable insights regarding noise phenomena in molecular wires and can be a powerful tool for the development of molecular electronic devices.

Enantiomerically enriched, polycrystalline molecular sieves

DOE PAGES

Brand, Stephen K.; Schmidt, Joel E.; Deem, Michael W.; ...

2017-05-01

Zeolite and zeolite-like molecular sieves are being used in a large number of applications such as adsorption and catalysis. Achievement of the long-standing goal of creating a chiral, polycrystalline molecular sieve with bulk enantioenrichment would enable these materials to perform enantioselective functions. Here, we report the synthesis of enantiomerically enriched samples of a molecular sieve. For this study, enantiopure organic structure directing agents are designed with the assistance of computational methods and used to synthesize enantioenriched, polycrystalline molecular sieve samples of either enantiomer. Computational results correctly predicted which enantiomer is obtained, and enantiomeric enrichment is proven by high-resolution transmission electronmore » microscopy. The enantioenriched and racemic samples of the molecular sieves are tested as adsorbents and heterogeneous catalysts. The enantioenriched molecular sieves show enantioselectivity for the ring opening reaction of epoxides and enantioselective adsorption of 2-butanol (the R enantiomer of the molecular sieve shows opposite and approximately equal enantioselectivity compared with the S enantiomer of the molecular sieve, whereas the racemic sample of the molecular sieve shows no enantioselectivity).« less

Enantiomerically enriched, polycrystalline molecular sieves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brand, Stephen K.; Schmidt, Joel E.; Deem, Michael W.

Zeolite and zeolite-like molecular sieves are being used in a large number of applications such as adsorption and catalysis. Achievement of the long-standing goal of creating a chiral, polycrystalline molecular sieve with bulk enantioenrichment would enable these materials to perform enantioselective functions. Here, we report the synthesis of enantiomerically enriched samples of a molecular sieve. For this study, enantiopure organic structure directing agents are designed with the assistance of computational methods and used to synthesize enantioenriched, polycrystalline molecular sieve samples of either enantiomer. Computational results correctly predicted which enantiomer is obtained, and enantiomeric enrichment is proven by high-resolution transmission electronmore » microscopy. The enantioenriched and racemic samples of the molecular sieves are tested as adsorbents and heterogeneous catalysts. The enantioenriched molecular sieves show enantioselectivity for the ring opening reaction of epoxides and enantioselective adsorption of 2-butanol (the R enantiomer of the molecular sieve shows opposite and approximately equal enantioselectivity compared with the S enantiomer of the molecular sieve, whereas the racemic sample of the molecular sieve shows no enantioselectivity).« less

Validation of nonlinear interferometric vibrational imaging as a molecular OCT technique by the use of Raman microscopy

NASA Astrophysics Data System (ADS)

Benalcazar, Wladimir A.; Jiang, Zhi; Marks, Daniel L.; Geddes, Joseph B.; Boppart, Stephen A.

2009-02-01

We validate a molecular imaging technique called Nonlinear Interferometric Vibrational Imaging (NIVI) by comparing vibrational spectra with those acquired from Raman microscopy. This broadband coherent anti-Stokes Raman scattering (CARS) technique uses heterodyne detection and OCT acquisition and design principles to interfere a CARS signal generated by a sample with a local oscillator signal generated separately by a four-wave mixing process. These are mixed and demodulated by spectral interferometry. Its confocal configuration allows the acquisition of 3D images based on endogenous molecular signatures. Images from both phantom and mammary tissues have been acquired by this instrument and its spectrum is compared with its spontaneous Raman signatures.

Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy

DTIC Science & Technology

2017-07-01

AWARD NUMBER: W81XWH-16-1-0194 TITLE: Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy PRINCIPAL...2017 4. TITLE AND SUBTITLE Molecular and Cellular Determinants of Malignant Transformation in Pulmonary Premalignancy 5a. CONTRACT NUMBER 5b. GRANT...Sequenced Regions Figure 2. Intra- and inter-patient genetic heterogeneity of pulmonary lesions. A) Distribution of Jaccard indices comparing n.s

Isochoric structural recovery in molecular glasses and its analog in colloidal glasses

NASA Astrophysics Data System (ADS)

Banik, Sourya; McKenna, Gregory B.

2018-06-01

Concentrated colloidal dispersions have been regarded as models for molecular glasses. One of the many ways to compare the behavior in these two different systems is by comparing the structural recovery or the physical aging behavior. However, recent investigations from our group to examine structural recovery in thermosensitive colloidal dispersions have shown contrasting results between the colloidal and the molecular glasses. The differences in the behaviors of the two systems have led us to pose this question: Is structural recovery behavior in colloidal glasses truly distinct from that of molecular glasses or is the conventional experimental condition (isobaric temperature-jumps) in determining the structural recovery in molecular glasses different from the experimental condition in the colloidal experiments (concentration- or volume fraction-jumps); i.e., are colloidal glasses inherently different from molecular glasses or not? To address the question, we resort to model calculations of structural recovery in a molecular glass under constant volume (isochoric) conditions following temperature only- and simultaneous volume- and temperature-jumps, which are closer to the volume fraction-jump conditions used in the thermosensitive-colloidal experiments. The current model predictions are then compared with the signatures of structural recovery under the conventional isobaric state in a molecular glass and with structural recovery behavior in colloidal glasses following volume fraction-jumps. We show that the results obtained from the experiments conducted by our group were contrasting to classical molecular glass behavior because the basis of our comparisons were incorrect (the histories were not analogous). The present calculations (with analogous histories) are qualitatively closer to the colloidal behavior. The signatures of "intrinsic isotherms" and "asymmetry of approach" in the current isochoric model predictions are quite different from those in the classical isobaric conditions while the "memory" signatures remain essentially the same. While there are qualitative similarities between the current isochoric model predictions and results from colloidal glasses, it appears from the calculations that the origins of these are different. The isochoric histories in the molecular glasses have compensating effects of pressure and departure from equilibrium which determines the structure dependence on mobility of the molecules. On the other hand, in the colloids it simply appears that the volume fraction-jump conditions simply do not exhibit such structure mobility dependence. The determining interplay of thermodynamic phase variables in colloidal and molecular systems might be very different or at least their correlations are yet to be ascertained. This topic requires further investigation to bring the similarities and differences between molecular and colloidal glass formers into fuller clarity.

Nanogap Electrodes towards Solid State Single-Molecule Transistors.

PubMed

Cui, Ajuan; Dong, Huanli; Hu, Wenping

2015-12-01

With the establishment of complementary metal-oxide-semiconductor (CMOS)-based integrated circuit technology, it has become more difficult to follow Moore's law to further downscale the size of electronic components. Devices based on various nanostructures were constructed to continue the trend in the minimization of electronics, and molecular devices are among the most promising candidates. Compared with other candidates, molecular devices show unique superiorities, and intensive studies on molecular devices have been carried out both experimentally and theoretically at the present time. Compared to two-terminal molecular devices, three-terminal devices, namely single-molecule transistors, show unique advantages both in fundamental research and application and are considered to be an essential part of integrated circuits based on molecular devices. However, it is very difficult to construct them using the traditional microfabrication techniques directly, thus new fabrication strategies are developed. This review aims to provide an exclusive way of manufacturing solid state gated nanogap electrodes, the foundation of constructing transistors of single or a few molecules. Such single-molecule transistors have the potential to be used to build integrated circuits. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparing the Atmospheric Losses at Io and Europa

NASA Astrophysics Data System (ADS)

Dols, V. J.; Bagenal, F.; Crary, F. J.; Cassidy, T.

2017-12-01

At Io and Europa, the interaction of the Jovian plasma with the moon atmosphere leads to a significant loss of atomic/molecular neutrals and ions to space. The processes that lead to atmospheric escape are diverse: atmospheric sputtering, molecular dissociation, molecular ion recombination, Jeans escape etc. Each process leads to neutrals escaping at different velocities (i.e. electron impact dissociation leads to very slow atomic neutrals, sputtering might eject faster molecular neutrals). Some neutrals will be ejected out of the Jovian system; others will form extended neutral clouds along the orbit of the moons. These atomic/molecular extended neutral clouds are probably the main source of plasma for the Jovian magnetosphere. They are difficult to observe directly thus their composition and density are still poorly constrained. A future modeling of the formation of these extended clouds requires an estimate of their atmospheric sources. We estimate the atmospheric losses at Io and Europa for each loss process with a multi-species chemistry model, using a prescribed atmospheric distribution consistent with the observations. We compare the neutral losses at Io and Europa.

Piezoelectric sensors based on molecular imprinted polymers for detection of low molecular mass analytes.

PubMed

Uludağ, Yildiz; Piletsky, Sergey A; Turner, Anthony P F; Cooper, Matthew A

2007-11-01

Biomimetic recognition elements employed for the detection of analytes are commonly based on proteinaceous affibodies, immunoglobulins, single-chain and single-domain antibody fragments or aptamers. The alternative supra-molecular approach using a molecularly imprinted polymer now has proven utility in numerous applications ranging from liquid chromatography to bioassays. Despite inherent advantages compared with biochemical/biological recognition (which include robustness, storage endurance and lower costs) there are few contributions that describe quantitative analytical applications of molecularly imprinted polymers for relevant small molecular mass compounds in real-world samples. There is, however, significant literature describing the use of low-power, portable piezoelectric transducers to detect analytes in environmental monitoring and other application areas. Here we review the combination of molecularly imprinted polymers as recognition elements with piezoelectric biosensors for quantitative detection of small molecules. Analytes are classified by type and sample matrix presentation and various molecularly imprinted polymer synthetic fabrication strategies are also reviewed.

Production of carbon molecular sieves from illinois coals. An assessment

USGS Publications Warehouse

Lizzio, Anthony A.; Rostam-Abadi, Massoud

1991-01-01

Chars were produced from an Illinois No. 2 bituminous coal under various pyrolysis and activation conditions and tested for their molecular sieve properties. The amount of N2 compared to the amount of CO2 adsorbed by each char was used as a preliminary indicator of its molecular sieve properties. This relatively simple, but apparently useful test was confirmed by successfully characterizing the well-known molecular sieve properties of a commercial zeolite and molecular sieve carbon. In addition, coal chars having relatively high surface areas (800-1800 m2/g) were produced and tested for their molecular sieving capabilities. These carbon materials, which have high adsorption capacities and relatively narrow pore size distributions, should be ideal candidates for the commercial production of CMS.

Methods for the quantitative comparison of molecular estimates of clade age and the fossil record.

PubMed

Clarke, Julia A; Boyd, Clint A

2015-01-01

Approaches quantifying the relative congruence, or incongruence, of molecular divergence estimates and the fossil record have been limited. Previously proposed methods are largely node specific, assessing incongruence at particular nodes for which both fossil data and molecular divergence estimates are available. These existing metrics, and other methods that quantify incongruence across topologies including entirely extinct clades, have so far not taken into account uncertainty surrounding both the divergence estimates and the ages of fossils. They have also treated molecular divergence estimates younger than previously assessed fossil minimum estimates of clade age as if they were the same as cases in which they were older. However, these cases are not the same. Recovered divergence dates younger than compared oldest known occurrences require prior hypotheses regarding the phylogenetic position of the compared fossil record and standard assumptions about the relative timing of morphological and molecular change to be incorrect. Older molecular dates, by contrast, are consistent with an incomplete fossil record and do not require prior assessments of the fossil record to be unreliable in some way. Here, we compare previous approaches and introduce two new descriptive metrics. Both metrics explicitly incorporate information on uncertainty by utilizing the 95% confidence intervals on estimated divergence dates and data on stratigraphic uncertainty concerning the age of the compared fossils. Metric scores are maximized when these ranges are overlapping. MDI (minimum divergence incongruence) discriminates between situations where molecular estimates are younger or older than known fossils reporting both absolute fit values and a number score for incompatible nodes. DIG range (divergence implied gap range) allows quantification of the minimum increase in implied missing fossil record induced by enforcing a given set of molecular-based estimates. These metrics are used together to describe the relationship between time trees and a set of fossil data, which we recommend be phylogenetically vetted and referred on the basis of apomorphy. Differences from previously proposed metrics and the utility of MDI and DIG range are illustrated in three empirical case studies from angiosperms, ostracods, and birds. These case studies also illustrate the ways in which MDI and DIG range may be used to assess time trees resultant from analyses varying in calibration regime, divergence dating approach or molecular sequence data analyzed. © The Author(s) 2014. Published by Oxford University Press, on behalf of the Society of Systematic Biologists. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cinnamaldehyde, Cinnamic Acid, and Cinnamyl Alcohol, the Bioactives of Cinnamomum cassia Exhibit HDAC8 Inhibitory Activity: An In vitro and In silico Study

PubMed Central

Patil, Mangesh; Choudhari, Amit S.; Pandita, Savita; Islam, Md Ataul; Raina, Prerna; Kaul-Ghanekar, Ruchika

2017-01-01

Background: The altered expression of histone deacetylase family member 8 (HDAC8) has been found to be linked with various cancers, thereby making its selective inhibition a potential strategy in cancer therapy. Recently, plant secondary metabolites, particularly phenolic compounds, have been shown to possess HDAC inhibitory activity. Objective: In the present work, we have evaluated the potential of cinnamaldehyde (CAL), cinnamic acid (CA), and cinnamyl alcohol (CALC) (bioactives of Cinnamomum) as well as aqueous cinnamon extract (ACE), to inhibit HDAC8 activity in vitro and in silico. Materials and Methods: HDAC8 inhibitory activity of ACE and cinnamon bioactives was determined in vitro using HDAC8 inhibitor screening kit. Trichostatin A (TSA), a well-known anti-cancer agent and HDAC inhibitor, was used as a positive control. In silico studies included molecular descriptor Analysis molecular docking absorption, distribution, metabolism, excretion, and toxicity prediction, density function theory calculation and synthetic accessibility program. Results: Pharmacoinformatics studies implicated that ACE and its Bioactives (CAL, CA, and CALC) exhibited comparable activity with that of TSA. The highest occupied molecular orbitals and lowest unoccupied molecular orbitals along with binding energy of cinnamon bioactives were comparable with that of TSA. Molecular docking results suggested that all the ligands maintained two hydrogen bond interactions within the active site of HDAC8. Finally, the synthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Conclusion: It was evident from both the experimental and computational data that cinnamon bioactives exhibited significant HDAC8 inhibitory activity, thereby suggesting their potential therapeutic implications against cancer. SUMMARY Pharmacoinformatics studies revealed that cinnamon bioactives bound to the active site of HDAC8 enzyme in a way similar to that of TSAThe molecular descriptors of cinnamon compounds successfully correlated with TSA values. The binding interactions and energies were also found to be close to TSASynthetic accessibility values showed that cinnamon bioactives were easy to synthesize compared to TSA. Abbreviations used: ACE: Aqueous Cinnamon Extract; DFT: Density Function Theory; CAL: Cinnamaldehyde; CA: Cinnamic Acid; CALC: Cinnamyl Alcohol; MW: Molecular Weight; ROTBs: Rotatable Bonds; ROF: Lipinski's Rule of Five; TSA: Trichostatin A; PDB: Protein Data Bank; RMSD: Root Mean Square Deviation; HBA: Hydrogen Bond Acceptor; HBD: Hydrogen Bond Donor; ADMET: Absorption, Distribution, Metabolism, Excretion and Toxicity; FO: Frontier Orbital; HOMOs: Highest Occupied Molecular Orbitals; LUMOs: Lowest Unoccupied Molecular Orbitals; BE: Binding Energy. PMID:29142427

Small business development for molecular diagnostics.

PubMed

Anagostou, Anthanasia; Liotta, Lance A

2012-01-01

Molecular profiling, which is the application of molecular diagnostics technology to tissue and blood -specimens, is an integral element in the new era of molecular medicine and individualized therapy. Molecular diagnostics is a fertile ground for small business development because it can generate products that meet immediate demands in the health-care sector: (a) Detection of disease risk, or early-stage disease, with a higher specificity and sensitivity compared to previous testing methods, and (b) "Companion diagnostics" for stratifying patients to receive a treatment choice optimized to their individual disease. This chapter reviews the promise and challenges of business development in this field. Guidelines are provided for the creation of a business model and the generation of a marketing plan around a candidate molecular diagnostic product. Steps to commercialization are outlined using existing molecular diagnostics companies as learning examples.

Molecular First Hyperpolarizabilities of a New Class of Asymmetric Squaraine Dyes

NASA Technical Reports Server (NTRS)

Chen, C. -T.; Marder, S. R.; Cheng, L. -T.

1993-01-01

The molecular first hyperpolarizabilities of a series of asymmetric squaraine dyes were measurd by electric-field-induced second harmonic generation; the dyes have negative -values whose magnitudes are comparable to 4-N,N-dimethylamino-4'-nitrostilbene (DANS).

Comparative Genomics Reveals Accelerated Evolution in Conserved Pathways during the Diversification of Anole Lizards.

PubMed

Tollis, Marc; Hutchins, Elizabeth D; Stapley, Jessica; Rupp, Shawn M; Eckalbar, Walter L; Maayan, Inbar; Lasku, Eris; Infante, Carlos R; Dennis, Stuart R; Robertson, Joel A; May, Catherine M; Crusoe, Michael R; Bermingham, Eldredge; DeNardo, Dale F; Hsieh, Shi-Tong Tonia; Kulathinal, Rob J; McMillan, William Owen; Menke, Douglas B; Pratt, Stephen C; Rawls, Jeffery Alan; Sanjur, Oris; Wilson-Rawls, Jeanne; Wilson Sayres, Melissa A; Fisher, Rebecca E; Kusumi, Kenro

2018-02-01

Squamates include all lizards and snakes, and display some of the most diverse and extreme morphological adaptations among vertebrates. However, compared with birds and mammals, relatively few resources exist for comparative genomic analyses of squamates, hampering efforts to understand the molecular bases of phenotypic diversification in such a speciose clade. In particular, the ∼400 species of anole lizard represent an extensive squamate radiation. Here, we sequence and assemble the draft genomes of three anole species-Anolis frenatus, Anolis auratus, and Anolis apletophallus-for comparison with the available reference genome of Anolis carolinensis. Comparative analyses reveal a rapid background rate of molecular evolution consistent with a model of punctuated equilibrium, and strong purifying selection on functional genomic elements in anoles. We find evidence for accelerated evolution in genes involved in behavior, sensory perception, and reproduction, as well as in genes regulating limb bud development and hindlimb specification. Morphometric analyses of anole fore and hindlimbs corroborated these findings. We detect signatures of positive selection across several genes related to the development and regulation of the forebrain, hormones, and the iguanian lizard dewlap, suggesting molecular changes underlying behavioral adaptations known to reinforce species boundaries were a key component in the diversification of anole lizards. © The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Evaluation of methods of determining humic acids in nucleic acid samples for molecular biological analysis.

PubMed

Wang, Yong; Fujii, Takeshi

2011-01-01

It is important in molecular biological analyses to evaluate contamination of co-extracted humic acids in DNA/RNA extracted from soil. We compared the sensitivity of various methods for measurement of humic acids, and influences of DNA/RNA and proteins on the measurement. Considering the results, we give suggestions as to choice of methods for measurement of humic acids in molecular biological analyses.

Effect of molecular topology on the transport properties of dendrimers in dilute solution at Θ temperature: A Brownian dynamics study

NASA Astrophysics Data System (ADS)

Bosko, Jaroslaw T.; Ravi Prakash, J.

2008-01-01

Structure and transport properties of dendrimers in dilute solution are studied with the aid of Brownian dynamics simulations. To investigate the effect of molecular topology on the properties, linear chain, star, and dendrimer molecules of comparable molecular weights are studied. A bead-spring chain model with finitely extensible springs and fluctuating hydrodynamic interactions is used to represent polymer molecules under Θ conditions. Structural properties as well as the diffusivity and zero-shear-rate intrinsic viscosity of polymers with varied degrees of branching are analyzed. Results for the free-draining case are compared to and found in very good agreement with the Rouse model predictions. Translational diffusivity is evaluated and the difference between the short-time and long-time behavior due to dynamic correlations is observed. Incorporation of hydrodynamic interactions is found to be sufficient to reproduce the maximum in the intrinsic viscosity versus molecular weight observed experimentally for dendrimers. Results of the nonequilibrium Brownian dynamics simulations of dendrimers and linear chain polymers subjected to a planar shear flow in a wide range of strain rates are also reported. The flow-induced molecular deformation of molecules is found to decrease hydrodynamic interactions and lead to the appearance of shear thickening. Further, branching is found to suppress flow-induced molecular alignment and deformation.

Towards a more molecular taxonomy of disease.

PubMed

Park, Jisoo; Hescott, Benjamin J; Slonim, Donna K

2017-07-27

Disease taxonomies have been designed for many applications, but they tend not to fully incorporate the growing amount of molecular-level knowledge of disease processes, inhibiting research efforts. Understanding the degree to which we can infer disease relationships from molecular data alone may yield insights into how to ultimately construct more modern taxonomies that integrate both physiological and molecular information. We introduce a new technique we call Parent Promotion to infer hierarchical relationships between disease terms using disease-gene data. We compare this technique with both an established ontology inference method (CliXO) and a minimum weight spanning tree approach. Because there is no gold standard molecular disease taxonomy available, we compare our inferred hierarchies to both the Medical Subject Headings (MeSH) category C forest of diseases and to subnetworks of the Disease Ontology (DO). This comparison provides insights about the inference algorithms, choices of evaluation metrics, and the existing molecular content of various subnetworks of MeSH and the DO. Our results suggest that the Parent Promotion method performs well in most cases. Performance across MeSH trees is also correlated between inference methods. Specifically, inferred relationships are more consistent with those in smaller MeSH disease trees than larger ones, but there are some notable exceptions that may correlate with higher molecular content in MeSH. Our experiments provide insights about learning relationships between diseases from disease genes alone. Future work should explore the prospect of disease term discovery from molecular data and how best to integrate molecular data with anatomical and clinical knowledge. This study nonetheless suggests that disease gene information has the potential to form an important part of the foundation for future representations of the disease landscape.

Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models

PubMed Central

Lindsey, Brooks D.; Shelton, Sarah E.; Foster, F. Stuart; Dayton, Paul A.

2017-01-01

Purpose To evaluate a new ultrasound molecular imaging approach in its ability to image a preclinical tumor model and to investigate the capacity to visualize and quantify co-registered microvascular and molecular imaging volumes. Procedures Molecular imaging using the new technique was compared with a conventional ultrasound molecular imaging technique (multi-pulse imaging) by varying the injected microbubble dose and scanning each animal using both techniques. Each of the 14 animals was randomly assigned one of three doses; bolus dose was varied, and the animals were imaged for three consecutive days so that each animal received every dose. A microvascular scan was also acquired for each animal by administering an infusion of non-targeted microbubbles. These scans were paired with co-registered molecular images (VEGFR2-targeted microbubbles), the vessels were segmented, and the spatial relationships between vessels and VEGFR2 targeting locations were analyzed. In 5 animals, an additional scan was performed in which the animal received a bolus of microbubbles targeted to E- and P-selectin. Vessel tortuosity as a function of distance from VEGF and selectin targeting was analyzed in these animals. Results Although resulting differences in image intensity due to varying microbubble dose were not significant between the two lowest doses, superharmonic imaging had significantly higher contrast-to-tissue ratio (CTR) than multi-pulse imaging (mean across all doses: 13.98 dB for molecular acoustic angiography vs. 0.53 dB for multi-pulse imaging; p = 4.9 × 10−10). Analysis of registered microvascular and molecular imaging volumes indicated that vessel tortuosity decreases with increasing distance from both VEGFR2 and selectin targeting sites. Conclusions Molecular acoustic angiography (superharmonic molecular imaging) exhibited a significant increase in CTR at all doses tested due to superior rejection of tissue artifact signals. Due to the high resolution of acoustic angiography molecular imaging, it is possible to analyze spatial relationships in aligned microvascular and molecular superharmonic imaging volumes. Future studies are required to separate the effects of biomarker expression and blood flow kinetics in comparing local tortuosity differences between different endothelial markers such as VEGFR2, E-selectin and P-selectin. PMID:27519522

Comparison of Molecular Typing Methods Useful for Detecting Clusters of Campylobacter jejuni and C. coli Isolates through Routine Surveillance

PubMed Central

Taboada, Eduardo; Grant, Christopher C. R.; Blakeston, Connie; Pollari, Frank; Marshall, Barbara; Rahn, Kris; MacKinnon, Joanne; Daignault, Danielle; Pillai, Dylan; Ng, Lai-King

2012-01-01

Campylobacter spp. may be responsible for unreported outbreaks of food-borne disease. The detection of these outbreaks is made more difficult by the fact that appropriate methods for detecting clusters of Campylobacter have not been well defined. We have compared the characteristics of five molecular typing methods on Campylobacter jejuni and C. coli isolates obtained from human and nonhuman sources during sentinel site surveillance during a 3-year period. Comparative genomic fingerprinting (CGF) appears to be one of the optimal methods for the detection of clusters of cases, and it could be supplemented by the sequencing of the flaA gene short variable region (flaA SVR sequence typing), with or without subsequent multilocus sequence typing (MLST). Different methods may be optimal for uncovering different aspects of source attribution. Finally, the use of several different molecular typing or analysis methods for comparing individuals within a population reveals much more about that population than a single method. Similarly, comparing several different typing methods reveals a great deal about differences in how the methods group individuals within the population. PMID:22162562

Adiabatic quantum computing with spin qubits hosted by molecules.

PubMed

Yamamoto, Satoru; Nakazawa, Shigeaki; Sugisaki, Kenji; Sato, Kazunobu; Toyota, Kazuo; Shiomi, Daisuke; Takui, Takeji

2015-01-28

A molecular spin quantum computer (MSQC) requires electron spin qubits, which pulse-based electron spin/magnetic resonance (ESR/MR) techniques can afford to manipulate for implementing quantum gate operations in open shell molecular entities. Importantly, nuclear spins, which are topologically connected, particularly in organic molecular spin systems, are client qubits, while electron spins play a role of bus qubits. Here, we introduce the implementation for an adiabatic quantum algorithm, suggesting the possible utilization of molecular spins with optimized spin structures for MSQCs. We exemplify the utilization of an adiabatic factorization problem of 21, compared with the corresponding nuclear magnetic resonance (NMR) case. Two molecular spins are selected: one is a molecular spin composed of three exchange-coupled electrons as electron-only qubits and the other an electron-bus qubit with two client nuclear spin qubits. Their electronic spin structures are well characterized in terms of the quantum mechanical behaviour in the spin Hamiltonian. The implementation of adiabatic quantum computing/computation (AQC) has, for the first time, been achieved by establishing ESR/MR pulse sequences for effective spin Hamiltonians in a fully controlled manner of spin manipulation. The conquered pulse sequences have been compared with the NMR experiments and shown much faster CPU times corresponding to the interaction strength between the spins. Significant differences are shown in rotational operations and pulse intervals for ESR/MR operations. As a result, we suggest the advantages and possible utilization of the time-evolution based AQC approach for molecular spin quantum computers and molecular spin quantum simulators underlain by sophisticated ESR/MR pulsed spin technology.

Long-term low-molecular-weight heparin and the post-thrombotic syndrome: a systematic review.

PubMed

Hull, Russell D; Liang, Jane; Townshend, Grace

2011-08-01

Post-thrombotic syndrome causes considerable morbidity. The Home-LITE study showed a lower incidence of post-thrombotic syndrome and venous ulcers after 3 months of treating deep vein thrombosis with the low-molecular-weight heparin tinzaparin versus oral anticoagulation. This systematic review examined whether long-term treatment of deep vein thrombosis using low-molecular-weight heparin, rather than oral anticoagulation, reduces development of post-thrombotic syndrome. We identified 9 articles comparing treatment of deep vein thrombosis using long-term low-molecular-weight heparin with any comparator, which reported outcomes relevant to the post-thrombotic syndrome assessed ≥ 3 months post-deep vein thrombosis. Pooled analysis of 2 studies yielded an 87% risk reduction with low-molecular-weight heparin in the incidence of venous ulcers at ≥ 3 months (P = .019). One study showed an overall odds ratio of 0.77 (P = .001) favoring low-molecular-weight heparin for the presence of 8 patient-reported post-thrombotic syndrome signs and symptoms. Pooled analysis of 5 studies showed a risk ratio for low-molecular-weight heparin versus oral anticoagulation of 0.66 (P < .0001) for complete recanalization of thrombosed veins. These results support the lower incidence of post-thrombotic syndrome and venous ulcers observed in Home-LITE. Long-term treatment with low-molecular-weight heparin rather than oral anticoagulation after a deep vein thrombosis may reduce or prevent development of signs and symptoms associated with post-thrombotic syndrome. Post-thrombotic syndrome and associated acute ulcers may develop more rapidly after deep vein thrombosis than previously recognized. Copyright © 2011 Elsevier Inc. All rights reserved.

DROIDS 1.20: A GUI-Based Pipeline for GPU-Accelerated Comparative Protein Dynamics.

PubMed

Babbitt, Gregory A; Mortensen, Jamie S; Coppola, Erin E; Adams, Lily E; Liao, Justin K

2018-03-13

Traditional informatics in comparative genomics work only with static representations of biomolecules (i.e., sequence and structure), thereby ignoring the molecular dynamics (MD) of proteins that define function in the cell. A comparative approach applied to MD would connect this very short timescale process, defined in femtoseconds, to one of the longest in the universe: molecular evolution measured in millions of years. Here, we leverage advances in graphics-processing-unit-accelerated MD simulation software to develop a comparative method of MD analysis and visualization that can be applied to any two homologous Protein Data Bank structures. Our open-source pipeline, DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations), works in conjunction with existing molecular modeling software to convert any Linux gaming personal computer into a "comparative computational microscope" for observing the biophysical effects of mutations and other chemical changes in proteins. DROIDS implements structural alignment and Benjamini-Hochberg-corrected Kolmogorov-Smirnov statistics to compare nanosecond-scale atom bond fluctuations on the protein backbone, color mapping the significant differences identified in protein MD with single-amino-acid resolution. DROIDS is simple to use, incorporating graphical user interface control for Amber16 MD simulations, cpptraj analysis, and the final statistical and visual representations in R graphics and UCSF Chimera. We demonstrate that DROIDS can be utilized to visually investigate molecular evolution and disease-related functional changes in MD due to genetic mutation and epigenetic modification. DROIDS can also be used to potentially investigate binding interactions of pharmaceuticals, toxins, or other biomolecules in a functional evolutionary context as well. Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.

MOLECULAR THERMODYNAMICS IN THE DESIGN OF SUBSTITUTE SOLVENTS

EPA Science Inventory

The use of physical properties and fluid behavior from molecular thermodynamics can lead to better decision making in the design of substitute solvents and can greatly reduce the expense and time required to find substitutes compared to designing solvents by experiment. this pape...

A molecular catalyst for water oxidation that binds to metal oxide surfaces

PubMed Central

Sheehan, Stafford W.; Thomsen, Julianne M.; Hintermair, Ulrich; Crabtree, Robert H.; Brudvig, Gary W.; Schmuttenmaer, Charles A.

2015-01-01

Molecular catalysts are known for their high activity and tunability, but their solubility and limited stability often restrict their use in practical applications. Here we describe how a molecular iridium catalyst for water oxidation directly and robustly binds to oxide surfaces without the need for any external stimulus or additional linking groups. On conductive electrode surfaces, this heterogenized molecular catalyst oxidizes water with low overpotential, high turnover frequency and minimal degradation. Spectroscopic and electrochemical studies show that it does not decompose into iridium oxide, thus preserving its molecular identity, and that it is capable of sustaining high activity towards water oxidation with stability comparable to state-of-the-art bulk metal oxide catalysts. PMID:25757425

Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrix–associated gene modules

PubMed Central

Balvers, Rutger K.; Kleijn, Anne; Kloezeman, Jenneke J.; French, Pim J.; Kremer, Andreas; van den Bent, Martin J.; Dirven, Clemens M. F.; Leenstra, Sieger; Lamfers, Martine L. M.

2013-01-01

Background Recent molecular characterization studies have identified clinically relevant molecular subtypes to coexist within the same histological entities of glioma. Comparative studies between serum-supplemented and serum-free (SF) culture conditions have demonstrated that SF conditions select for glioma stem-like cells, which superiorly conserve genomic alterations. However, neither the representation of molecular subtypes within SF culture assays nor the molecular distinctions between successful and nonsuccessful attempts have been elucidated. Methods A cohort of 261 glioma samples from varying histological grades was documented for SF culture success and clinical outcome. Gene expression and single nucleotide polymorphism arrays were interrogated on a panel of tumors for comparative analysis of SF+ (successful cultures) and SF− (unsuccessful cultures). Results SF culture outcome was correlated with tumor grade, while no relation was found between SF+ and patient overall survival. Copy number–based hierarchical clustering revealed an absolute separation between SF+ and SF− parental tumors. All SF+ cultures are derived from tumors that are isocitrate dehydrogenase 1 (IDH1) wild type, chromosome 7 amplified, and chromosome 10q deleted. SF− cultures derived from IDH1 mutant tumors demonstrated a fade-out of mutated cells during the first passages. SF+ tumors were enriched for The Cancer Genome Atlas Classical subtype and intrinsic glioma subtype-18. Comparative gene ontology analysis between SF+ and SF− tumors demonstrated enrichment for modules associated with extracellular matrix composition, Hox-gene signaling, and inflammation. Conclusion SF cultures are derived from a subset of parental tumors with a shared molecular background including enrichment for extracellular matrix–associated gene modules. These results provide leads to develop enhanced culture protocols for glioma samples not propagatable under current SF conditions. PMID:24046260

Galaxy pairs in the SDSS - XIII. The connection between enhanced star formation and molecular gas properties in galaxy mergers

NASA Astrophysics Data System (ADS)

Violino, Giulio; Ellison, Sara L.; Sargent, Mark; Coppin, Kristen E. K.; Scudder, Jillian M.; Mendel, Trevor J.; Saintonge, Amelie

2018-05-01

We investigate the connection between star formation and molecular gas properties in galaxy mergers at low redshift (z ≤ 0.06). The study we present is based on IRAM 30-m CO(1-0) observations of 11 galaxies with a close companion selected from the Sloan Digital Sky Survey (SDSS). The pairs have mass ratios ≤4, projected separations rp ≤ 30 kpc and velocity separations ΔV ≤ 300 km s-1, and have been selected to exhibit enhanced specific star formation rates (sSFRs). We calculate molecular gas (H2) masses, assigning to each galaxy a physically motivated conversion factor αCO, and we derive molecular gas fractions and depletion times. We compare these quantities with those of isolated galaxies from the extended CO Legacy Data base for the GALEX Arecibo SDSS Survey sample (xCOLDGASS; Saintonge et al.) with gas quantities computed in an identical way. Ours is the first study which directly compares the gas properties of galaxy pairs and those of a control sample of normal galaxies with rigorous control procedures and for which SFR and H2 masses have been estimated using the same method. We find that the galaxy pairs have shorter depletion times and an average molecular gas fraction enhancement of 0.4 dex compared to the mass matched control sample drawn from xCOLDGASS. However, the gas masses (and fractions) in galaxy pairs and their depletion times are consistent with those of non-mergers whose SFRs are similarly elevated. We conclude that both external interactions and internal processes may lead to molecular gas enhancement and decreased depletion times.

Molecular classification of patients with grade II/III glioma using quantitative MRI characteristics.

PubMed

Bahrami, Naeim; Hartman, Stephen J; Chang, Yu-Hsuan; Delfanti, Rachel; White, Nathan S; Karunamuni, Roshan; Seibert, Tyler M; Dale, Anders M; Hattangadi-Gluth, Jona A; Piccioni, David; Farid, Nikdokht; McDonald, Carrie R

2018-06-02

Molecular markers of WHO grade II/III glioma are known to have important prognostic and predictive implications and may be associated with unique imaging phenotypes. The purpose of this study is to determine whether three clinically relevant molecular markers identified in gliomas-IDH, 1p/19q, and MGMT status-show distinct quantitative MRI characteristics on FLAIR imaging. Sixty-one patients with grade II/III gliomas who had molecular data and MRI available prior to radiation were included. Quantitative MRI features were extracted that measured tissue heterogeneity (homogeneity and pixel correlation) and FLAIR border distinctiveness (edge contrast; EC). T-tests were conducted to determine whether patients with different genotypes differ across the features. Logistic regression with LASSO regularization was used to determine the optimal combination of MRI and clinical features for predicting molecular subtypes. Patients with IDH wildtype tumors showed greater signal heterogeneity (p = 0.001) and lower EC (p = 0.008) within the FLAIR region compared to IDH mutant tumors. Among patients with IDH mutant tumors, 1p/19q co-deleted tumors had greater signal heterogeneity (p = 0.002) and lower EC (p = 0.005) compared to 1p/19q intact tumors. MGMT methylated tumors showed lower EC (p = 0.03) compared to the unmethylated group. The combination of FLAIR border distinctness, heterogeneity, and pixel correlation optimally classified tumors by IDH status. Quantitative imaging characteristics of FLAIR heterogeneity and border pattern in grade II/III gliomas may provide unique information for determining molecular status at time of initial diagnostic imaging, which may then guide subsequent surgical and medical management.

An Integrated Approach to Rapid Diagnosis of Tuberculosis and Multidrug Resistance Using Liquid Culture and Molecular Methods in Russia

PubMed Central

Balabanova, Yanina; Drobniewski, Francis; Nikolayevskyy, Vladyslav; Kruuner, Annika; Malomanova, Nadezhda; Simak, Tatyana; Ilyina, Nailya; Zakharova, Svetlana; Lebedeva, Natalya; Alexander, Heather L.; O'Brien, Rick; Sohn, Hojoon; Shakhmistova, Anastasia; Fedorin, Ivan

2009-01-01

Objective To analyse the feasibility, cost and performance of rapid tuberculosis (TB) molecular and culture systems, in a high multidrug-resistant TB (MDR TB) middle-income region (Samara, Russia) and provide evidence for WHO policy change. Methods Performance and cost evaluation was conducted to compare the BACTEC™ MGIT™ 960 system for culture and drug susceptibility testing (DST) and molecular systems for TB diagnosis, resistance to isoniazid and rifampin, and MDR TB identification compared to conventional Lowenstein-Jensen culture assays. Findings 698 consecutive patients (2487 sputum samples) with risk factors for drug-resistant tuberculosis were recruited. Overall M. tuberculosis complex culture positivity rates were 31.6% (787/2487) in MGIT and 27.1% (675/2487) in LJ (90.5% and 83.2% for smear-positive specimens). In total, 809 cultures of M. tuberculosis complex were isolated by any method. Median time to detection was 14 days for MGIT and 36 days for LJ (10 and 33 days for smear positive specimens) and indirect DST in MGIT took 9 days compared to 21 days on LJ. There was good concordance between DST on LJ and MGIT (96.8% for rifampin and 95.6% for isoniazid). Both molecular hybridization assay results correlated well with MGIT DST results, although molecular assays generally yielded higher rates of resistance (by approximately 3% for both isoniazid and rifampin). Conclusion With effective planning and logistics, the MGIT 960 and molecular based methodologies can be successfully introduced into a reference laboratory setting in a middle incidence country. High rates of MDR TB in the Russian Federation make the introduction of such assays particularly useful. PMID:19774085

Ultrahigh molecular weight aromatic siloxane polymers

NASA Technical Reports Server (NTRS)

Ludwick, L. M.

1982-01-01

The condensation of a diol with a silane in toluene yields a silphenylene-siloxane polymer. The reaction of stiochiometric amounts of the diol and silane produced products with molecular weights in the range 2.0 - 6.0 x 10 to the 5th power. The molecular weight of the product was greatly increased by a multistep technique. The methodology for synthesis of high molecular weight polymers using a two step procedure was refined. Polymers with weight average molecular weights in excess of 1.0 x 10 to the 6th power produced by this method. Two more reactive silanes, bis(pyrrolidinyl)dimethylsilane and bis(gamma butyrolactam)dimethylsilane, are compared with the dimethyleminodimethylsilane in ability to advance the molecular weight of the prepolymer. The polymers produced are characterized by intrinsic viscosity in tetrahydrofuran. Weight and number average molecular weights and polydispersity are determined by gel permeation chromatography.

Tumorigenic action of beta, proton, alpha and electron radiation on the rat skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burns, F.J.

1980-01-01

Rat skin is utilized as a model system for studying dose and time related aspects of the oncogenic action of ionizing radiation, ultraviolet light and polycyclic aromatic hydrocarbons. Molecular lesions in the DNA of the epidermis, including strand breaks and thymine dimers, are measured and compared to the temporal and dose related aspects of tumor induction. The induction and repair kinetics of molecular lesions are compared to split dose recovery as modified by sensitizers and type of radition of oncogenic damage.

Comparison of selected analytical techniques for protein sizing, quantitation and molecular weight determination.

PubMed

Goetz, H; Kuschel, M; Wulff, T; Sauber, C; Miller, C; Fisher, S; Woodward, C

2004-09-30

Protein analysis techniques are developing fast due to the growing number of proteins obtained by recombinant DNA techniques. In the present paper we compare selected techniques, which are used for protein sizing, quantitation and molecular weight determination: sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE), lab-on-a-chip or microfluidics technology (LoaC), size exclusion chromatography (SEC) and mass spectrometry (MS). We compare advantages and limitations of each technique in respect to different application areas, analysis time, protein sizing and quantitation performance.

Physical characterization of polyethylene glycols by thermal analytical technique and the effect of humidity and molecular weight.

PubMed

Majumdar, R; Alexander, K S; Riga, A T

2010-05-01

Polyethylene glycols (PEGs) are well known as excipients in tablet dosage formulations. PEGs are generally known to be inert and have very few interactions with other components in the solid dosage forms. However, the physical nature of PEGs and how they affect the disintegration of tablets is not very well understood for the different molecular weights of PEGs. The knowledge of the effect of molecular weight of PEGs on their physical properties and the effect of humidity on the physical properties of PEGs are important parameters for the choice of a PEG to be acceptable as an excipient in pharmaceutical formulations. This study was done to determine the precision of the DSC physical properties for a wide range of PEGs with varying molecular weights from 194 to 23000 daltons. Nine different molecular weights of PEGs were examined in a DSC controlled Heat-Cool-Heat-Cool-Heat (HCHCH) cycle and the observed reproducible values of melting temperature, heat of fusion, crystallization temperature and the heat of crystallization were compared with values obtained from the literature and the observed percent crystallinity was again cross-checked by X-ray Diffraction (XRD) studies. The comparison values indicated acceptable precision. This study was also done to check the effect of humidity on the DSC physical properties for the entire range of PEGs. The results indicated that humidity probably has a higher effect on the physical properties of the low molecular weight PEGs as compared to the high molecular weight PEGs.

Molecular profiling--a tool for addressing emerging gaps in the comparative risk assessment of GMOs.

PubMed

Heinemann, Jack A; Kurenbach, Brigitta; Quist, David

2011-10-01

Assessing the risks of genetically modified organisms (GMOs) is required by both international agreement and domestic legislation. Many view the use of the "omics" tools for profiling classes of molecules as useful in risk assessment, but no consensus has formed on the need or value of these techniques for assessing the risks of all GMOs. In this and many other cases, experts support case-by-case use of molecular profiling techniques for risk assessment. We review the latest research on the applicability and usefulness of molecular profiling techniques for GMO risk assessment. As more and more kinds of GMOs and traits are developed, broader use of molecular profiling in a risk assessment may be required to supplement the comparative approach to risk assessment. The literature-based discussions on the use of profiling appear to have settled on two findings: 1. profiling techniques are reliable and relevant, at least no less so than other techniques used in risk assessment; and 2. although not required routinely, regulators should be aware of when they are needed. The dismissal of routine molecular profiling may be confusing to regulators who then lack guidance on when molecular profiling might be worthwhile. Molecular profiling is an important way to increase confidence in risk assessments if the profiles are properly designed to address relevant risks and are applied at the correct stage of the assessment. Copyright © 2011 Elsevier Ltd. All rights reserved.

The role of inhibition by phosphocitrate and its analogue in chondrocyte differentiation and subchondral bone advance in Hartley guinea pigs

PubMed Central

Sun, Yubo; Kiraly, Alex J.; Cox, Michael; Mauerhan, David R.; Hanley, Edward N.

2018-01-01

Phosphocitrate (PC) and its analogue, PC-β ethyl ester, inhibit articular cartilage degeneration in Hartley guinea pigs. However, the underlying molecular mechanisms remain unclear. The present study aimed to investigate the hypothesis that PC exerted its disease-modifying effect on osteoarthritis (OA), in part, by inhibiting a molecular program similar to that in the endochondral pathway of ossification. The results demonstrated that severe proteoglycan loss occurred in the superficial and middle zones, as well as in the calcified zone of articular cartilage in the Hartley guinea pigs. Subchondral bone advance was greater in the control Hartley guinea pigs compared with PC- or PC analogue-treated guinea pigs. Resorption of cartilage bars or islands and vascular invasion in the growth plate were also greater in the control guinea pigs compared with the PC- or PC analogue-treated guinea pigs. The levels of matrix metalloproteinase-13 and type X collagen within the articular cartilage and growth plate were significantly increased in the control guinea pigs compared with PC-treated guinea pigs (P<0.05). These results indicated that articular chondrocytes in Hartley guinea pigs exhibited a hypertrophic phenotype and recapitulated a developmental molecular program similar to the endochondral pathway of ossification. Activation of this molecular program resulted in resorption of calcified articular cartilage and subchondral bone advance. This suggests that PC and PC analogues exerted their OA disease-modifying activity, in part, by inhibiting this molecular program. PMID:29545850

Differences in molecular characteristics between Cronartium quercuum from Japan and fusiform rust from USA

Treesearch

Hitoshi Nakamura; Shigeru Kaneko; Pauline Spaine

1998-01-01

The molecular characteristics were compared among Cronartium quercuum f. sp. densiflorae and C. quercuum f. sp. thunbergii from Japan and C. quercuum f. sp. fusiforme, fusiform rust from the USA. The authors examined the PCR-amplified internal transcribed...

State-selective charge exchange in slow collisions of Si3+ ions with H atoms: A molecular state close coupling treatment*)

NASA Astrophysics Data System (ADS)

Joseph, Dwayne C.; Saha, Bidhan C.

2012-11-01

Charge transfer cross sections are calculated by employing both the quantal and semiclassical ɛ(R) molecular orbital close coupling (MOCC) approximations in the adiabatic representation and compared with other theoretical and experimental results

Molecular docking and spectroscopic investigations aided by density functional theory of Parkinson's drug 2-(3,4-dihydroxyphenyl)ethylamine

NASA Astrophysics Data System (ADS)

Sherlin, Y. Sheeba; Vijayakumar, T.; Roy, S. D. D.; Jayakumar, V. S.

2018-05-01

Molecular geometry of Parkinson's drug 2-(3,4-Dihydroxyphenyl)ethylamine hydrochloride (Dopamine, DA) has been evaluated and compared with experimental XRD data. Molecular docking and vibrational spectral analysis of DA have been carried out using FT-Raman and FT-IR spectra aided by Density Functional Theory at B3LYP/6-311++G(d,p). The present investigation deals with the analysis of structural and spectral features responsible for drug activities, nature of hydrogen bonding interactions of the molecule and the correlation of Parkinson's nature with its molecular structural features.

A comparative molecular dynamics study on thermostability of human and chicken prion proteins

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ji, Hong-Fang; Zhang, Hong-Yu

To compare the thermostabilities of human and chicken normal cellular prion proteins (HuPrP{sup C} and CkPrP{sup C}), molecular dynamics (MD) simulations were performed for both proteins at an ensemble level (10 parallel simulations at 400 K and 5 parallel simulations at 300 K as a control). It is found that the thermostability of HuPrP{sup C} is comparable with that of CkPrP{sup C}, which implicates that the non-occurrence of prion diseases in non-mammals cannot be completely attributed to the thermodynamic properties of non-mammalian PrP{sup C}.

A 17 GHz molecular rectifier

PubMed Central

Trasobares, J.; Vuillaume, D.; Théron, D.; Clément, N.

2016-01-01

Molecular electronics originally proposed that small molecules sandwiched between electrodes would accomplish electronic functions and enable ultimate scaling to be reached. However, so far, functional molecular devices have only been demonstrated at low frequency. Here, we demonstrate molecular diodes operating up to 17.8 GHz. Direct current and radio frequency (RF) properties were simultaneously measured on a large array of molecular junctions composed of gold nanocrystal electrodes, ferrocenyl undecanethiol molecules and the tip of an interferometric scanning microwave microscope. The present nanometre-scale molecular diodes offer a current density increase by several orders of magnitude compared with that of micrometre-scale molecular diodes, allowing RF operation. The measured S11 parameters show a diode rectification ratio of 12 dB which is linked to the rectification behaviour of the direct current conductance. From the RF measurements, we extrapolate a cut-off frequency of 520 GHz. A comparison with the silicon RF-Schottky diodes, architecture suggests that the RF-molecular diodes are extremely attractive for scaling and high-frequency operation. PMID:27694833

Ultrafast and nonlinear spectroscopy of brilliant green-based nanoGUMBOS with enhanced near-infrared emission

NASA Astrophysics Data System (ADS)

Karam, Tony E.; Siraj, Noureen; Zhang, Zhenyu; Ezzir, Abdulrahman F.; Warner, Isiah M.; Haber, Louis H.

2017-10-01

The synthesis, characterization, ultrafast dynamics, and nonlinear spectroscopy of 30 nm nanospheres of brilliant green-bis(pentafluoroethylsulfonyl)imide ([BG][BETI]) in water are reported. These thermally stable nanoparticles are derived from a group of uniform materials based on organic salts (nanoGUMBOS) that exhibit enhanced near-infrared emission compared with the molecular dye in water. The examination of ultrafast transient absorption spectroscopy results reveals that the overall excited-state relaxation lifetimes of [BG][BETI] nanoGUMBOS are longer than the brilliant green molecular dye in water due to steric hindrance of the torsional degrees of freedom of the phenyl rings around the central carbon. Furthermore, the second harmonic generation signal of [BG][BETI] nanoGUMBOS is enhanced by approximately 7 times and 23 times as compared with colloidal gold nanoparticles of the same size and the brilliant green molecular dye in water, respectively. A very clear third harmonic generation signal is observed from the [BG][BETI] nanoGUMBOS but not from either the molecular dye or the gold nanoparticles. Overall, these results show that [BG][BETI] nanoGUMBOS exhibit altered ultrafast and nonlinear spectroscopy that is beneficial for various applications including nonlinear imaging probes, biomedical imaging, and molecular sensing.

Molecular weight, polydispersity, and spectroscopic properties of aquatic humic substances

USGS Publications Warehouse

Chin, Y.-P.; Aiken, G.; O'Loughlin, E.

1994-01-01

The number- and weight-averaged molecular weights of a number of aquatic fulvic acids, a commercial humic acid, and unfractionated organic matter from four natural water samples were measured by high-pressure size exclusion chromatography (HPSEC). Molecular weights determined in this manner compared favorably with those values reported in the literature. Both recent literature values and our data indicate that these substances are smaller and less polydisperse than previously believed. Moreover, the molecular weights of the organic matter from three of the four natural water samples compared favorably to the fulvic acid samples extracted from similar environments. Bulk spectroscopic properties of the fulvic substances such as molar absorptivity at 280 nm and the E4/E6 ratio were also measured. A strong correlation was observed between molar absorptivity, total aromaticity, and the weight average molecular weights of all the humic substances. This observation suggests that bulk spectroscopic properties can be used to quickly estimate the size of humic substances and their aromatic contents. Both parameters are important with respect to understanding humic substance mobility and their propensity to react with both organic and inorganic pollutants. ?? 1994 American Chemical Society.

Mapping Hydrophobicity on the Protein Molecular Surface at Atom-Level Resolution

PubMed Central

Nicolau Jr., Dan V.; Paszek, Ewa; Fulga, Florin; Nicolau, Dan V.

2014-01-01

A precise representation of the spatial distribution of hydrophobicity, hydrophilicity and charges on the molecular surface of proteins is critical for the understanding of the interaction with small molecules and larger systems. The representation of hydrophobicity is rarely done at atom-level, as this property is generally assigned to residues. A new methodology for the derivation of atomic hydrophobicity from any amino acid-based hydrophobicity scale was used to derive 8 sets of atomic hydrophobicities, one of which was used to generate the molecular surfaces for 35 proteins with convex structures, 5 of which, i.e., lysozyme, ribonuclease, hemoglobin, albumin and IgG, have been analyzed in more detail. Sets of the molecular surfaces of the model proteins have been constructed using spherical probes with increasingly large radii, from 1.4 to 20 Å, followed by the quantification of (i) the surface hydrophobicity; (ii) their respective molecular surface areas, i.e., total, hydrophilic and hydrophobic area; and (iii) their relative densities, i.e., divided by the total molecular area; or specific densities, i.e., divided by property-specific area. Compared with the amino acid-based formalism, the atom-level description reveals molecular surfaces which (i) present an approximately two times more hydrophilic areas; with (ii) less extended, but between 2 to 5 times more intense hydrophilic patches; and (iii) 3 to 20 times more extended hydrophobic areas. The hydrophobic areas are also approximately 2 times more hydrophobicity-intense. This, more pronounced “leopard skin”-like, design of the protein molecular surface has been confirmed by comparing the results for a restricted set of homologous proteins, i.e., hemoglobins diverging by only one residue (Trp37). These results suggest that the representation of hydrophobicity on the protein molecular surfaces at atom-level resolution, coupled with the probing of the molecular surface at different geometric resolutions, can capture processes that are otherwise obscured to the amino acid-based formalism. PMID:25462574

Molecular Dynamics Approach in Designing Thermostable Aspergillus niger Xylanase

NASA Astrophysics Data System (ADS)

Malau, N. D.; Sianturi, M.

2017-03-01

Molecular dynamics methods we have applied as a tool in designing thermostable Aspergillus niger Xylanase, by examining Root Mean Square Deviation (RMSD) and The Stability of the Secondary Structure of enzymes structure at its optimum temperature and compare with its high temperature behavior. As RMSD represents structural fluctuation at a particular temperature, a better understanding of this factor will suggest approaches to bioengineer these enzymes to enhance their thermostability. In this work molecular dynamic simulations of Aspergillus niger xylanase (ANX) have been carried at 400K (optimum catalytic temperature) for 2.5 ns and 500K (ANX reported inactive temperature) for 2.5 ns. Analysis have shown that the Root Mean Square Deviation (RMSD) significant increase at higher temperatures compared at optimum temperature and some of the secondary structures of ANX that have been damaged at high temperature. Structural analysis revealed that the fluctuations of the α-helix and β-sheet regions are larger at higher temperatures compared to the fluctuations at optimum temperature.

Reading the Molecular Clock.

ERIC Educational Resources Information Center

McKean, Kevin

1983-01-01

Suggesting that the evolutionary record may be written in proteins and genes, discusses research in which species are compared by immunology, DNA, and radioimmunoassay. Molecular studies show that DNA from humans and chimps is 98 percent identical, a degree of similarity usually occurring only among animals of the same genus. (JN)

75 FR 51280 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-19

... Special Emphasis Panel; Member Conflict: Cellular and Molecular Aspects of Neurodevelopment. Date... Group; Cellular and Molecular Immunology--A Study Section. Date: September 30-October 1, 2010. Time: [email protected] . (Catalogue of Federal Domestic Assistance Program Nos. 93.306, Comparative Medicine; 93.333...

Molecular Diagnostics of the Internal Structure of Starspots and Sunspots

NASA Astrophysics Data System (ADS)

Afram, N.; Berdyugina, S. V.; Fluri, D. M.; Solanki, S. K.; Lagg, A.; Petit, P.; Arnaud, J.

2006-12-01

We have analyzed the usefulness of molecules as a diagnostic tool for studying solar and stellar magnetism with the molecular Zeeman and Paschen-Back effects. In the first part we concentrate on molecules that are observed in sunspots such as MgH and TiO. We present calculated molecular line profiles obtained by assuming magnetic fields of 2-3 kG and compare these synthetic Stokes profiles with spectro-polarimetric observations in sunspots. The good agreement between the theory and observations allows us to turn our attention in the second part to starspots to gain insight into their internal structure. We investigate the temperature range in which the selected molecules can serve as indicators for magnetic fields on highly active cool stars and compare synthetic Stokes profiles with our recent observations.

Comparative Analysis of Proteomes and Functionomes Provides Insights into Origins of Cellular Diversification

PubMed Central

Caetano-Anollés, Gustavo

2013-01-01

Reconstructing the evolutionary history of modern species is a difficult problem complicated by the conceptual and technical limitations of phylogenetic tree building methods. Here, we propose a comparative proteomic and functionomic inferential framework for genome evolution that allows resolving the tripartite division of cells and sketching their history. Evolutionary inferences were derived from the spread of conserved molecular features, such as molecular structures and functions, in the proteomes and functionomes of contemporary organisms. Patterns of use and reuse of these traits yielded significant insights into the origins of cellular diversification. Results uncovered an unprecedented strong evolutionary association between Bacteria and Eukarya while revealing marked evolutionary reductive tendencies in the archaeal genomic repertoires. The effects of nonvertical evolutionary processes (e.g., HGT, convergent evolution) were found to be limited while reductive evolution and molecular innovation appeared to be prevalent during the evolution of cells. Our study revealed a strong vertical trace in the history of proteins and associated molecular functions, which was reliably recovered using the comparative genomics approach. The trace supported the existence of a stem line of descent and the very early appearance of Archaea as a diversified superkingdom, but failed to uncover a hidden canonical pattern in which Bacteria was the first superkingdom to deploy superkingdom-specific structures and functions. PMID:24492748

Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium

PubMed Central

Lawrenson, Kate; Pakzamir, Elham; Liu, Biao; Lee, Janet M.; Delgado, Melissa K.; Duncan, Kara; Gayther, Simon A.; Liu, Song; Roman, Lynda; Mhawech-Fauceglia, Paulette

2015-01-01

Background The molecular biology and cellular origins of mixed type endometrial carcinomas (MT-ECs) are poorly understood, and a Type II component of 10 percent or less may confer poorer prognoses. Methodology/Principal Findings We studied 10 cases of MT-EC (containing endometrioid and serous differentiation), 5 pure low-grade endometrioid adenocarcinoma (EAC) and 5 pure uterine serous carcinoma (USC). Endometrioid and serous components of the MT-ECs were macrodissected and the expression of 60 candidate genes compared between MT-EC, pure USC and pure EAC. We found that four genes were differentially expressed when MT-ECs were compared to pure low-grade EAC: CDKN2A (P = 0.006), H19 (P = 0.010), HOMER2 (P = 0.009) and TNNT1 (P = 0.006). Also while we found that even though MT-ECs closely resembled the molecular profiles of pure USCs, they also exhibit lower expression of PAX8 compared to all pure cases combined (P = 0.035). Conclusion Our data suggest that MT-EC exhibits the closest molecular and epidemiological similarities to pure USC and supports clinical observations that suggest patients with MT-EC should receive the same treatment as patients with pure serous carcinoma. Novel specific markers of MT-EC could be of diagnostic utility and could represent novel therapeutic targets in the future. PMID:26132201

Molecular dynamics in principal component space.

PubMed

Michielssens, Servaas; van Erp, Titus S; Kutzner, Carsten; Ceulemans, Arnout; de Groot, Bert L

2012-07-26

A molecular dynamics algorithm in principal component space is presented. It is demonstrated that sampling can be improved without changing the ensemble by assigning masses to the principal components proportional to the inverse square root of the eigenvalues. The setup of the simulation requires no prior knowledge of the system; a short initial MD simulation to extract the eigenvectors and eigenvalues suffices. Independent measures indicated a 6-7 times faster sampling compared to a regular molecular dynamics simulation.

A molecular model for proflavine-DNA intercalation.

PubMed Central

Neidle, S; Pearl, L H; Herzyk, P; Berman, H M

1988-01-01

A molecular model has been derived for the intercalation of proflavine into the CpG site of the decamer duplex of d(GATACGATAC). The starting geometry of the intercalation site was taken from previous crystallographic studies on the d(CpG)-proflavine complex, and molecular mechanics used to obtain a stereochemically acceptable structure. This has widened grooves compared to standard A- or B- double helices, as well as distinct conformational, roll, twist and tilt features. PMID:3174439

Second harmonic generation in a molecular magnetic chain

NASA Astrophysics Data System (ADS)

Cavigli, L.; Sessoli, R.; Gurioli, M.; Bogani, L.

2006-05-01

A setup for the determination of all the components of the second harmonic generation tensor in molecular materials is presented. It allows overcoming depletion problems, which one can expect to be common in molecular systems. A preliminary characterization of the nonlinear properties of the single chain magnet CoPhOMe is carried out. We observe a high second harmonic signal, comparable to that of urea, and show that the bulk contributions are dominant over the surface ones.

Effects of the Shuttle Orbiter fuselage and elevon on the molecular distribution of water vapor from the flash evaporator system

NASA Technical Reports Server (NTRS)

Richmond, R. G.; Kelso, R. M.

1980-01-01

A concern has arisen regarding the emissive distribution of water molecules from the shuttle orbiter flash evaporator system (FES). The role of the orbiter fuselage and elevon in affecting molecular scattering distributions was nuclear. The effect of these components were evaluated. Molecular distributions of the water vapor effluents from the FE were measured. These data were compared with analytically predicted values and the resulting implications were calculated.

Optoelectronic Materials Center, A Collaborative Program Including University of New Mexico, Stanford University and California Institute of Technology

DTIC Science & Technology

1992-06-30

in the film. Ion-assisted molecular beam epitaxy is one of a class of techniques that allow modification growth kinetics during heteroepitaxy, with...the potential for novel means of misfit accommodation. In the last quarter, using ion-assisted molecular beam epitaxy , we have demonstrated 1. Reduction...shown in Figure 1. The results are compared with single quantum well material grown by Molecular Beam Epitaxy (MBE) previously. The optimum cavity

Sodium pump molecular activity and membrane lipid composition in two disparate ectotherms, and comparison with endotherms.

PubMed

Turner, Nigel; Hulbert, A J; Else, Paul L

2005-02-01

Previous research has shown that the lower sodium pump molecular activity observed in tissues of ectotherms compared to endotherms, is largely related to the lower levels of polyunsaturates and higher levels of monounsaturates found in the cell membranes of ectotherms. Marine-based ectotherms, however, have very polyunsaturated membranes, and in the current study, we measured molecular activity and membrane lipid composition in tissues of two disparate ectothermic species, the octopus (Octopus vulgaris) and the bearded dragon lizard (Pogona vitticeps), to determine whether the high level of membrane polyunsaturation generally observed in marine-based ectotherms is associated with an increased sodium pump molecular activity relative to other ectotherms. Phospholipids from all tissues of the octopus were highly polyunsaturated and contained high concentrations of the omega-3 polyunsaturate, docosahexaenoic acid (22:6 (n-3)). In contrast, phospholipids from bearded dragon tissues contained higher proportions of monounsaturates and lower proportions of polyunsaturates. Sodium pump molecular activity was only moderately elevated in tissues of the octopus compared to the bearded dragon, despite the much greater level of polyunsaturation in octopus membranes. When the current data were combined with data for the ectothermic cane toad, a significant (P = 0.003) correlation was observed between sodium pump molecular activity and the content of 22:6 (n-3) in the surrounding membrane. These results are discussed in relation to recent work which shows a similar relationship in endotherms.

Lubricant shear thinning behavior correlated with variation of radius of gyration via molecular dynamics simulations

NASA Astrophysics Data System (ADS)

Liu, Pinzhi; Lu, Jie; Yu, Hualong; Ren, Ning; Lockwood, Frances E.; Wang, Q. Jane

2017-08-01

The shear thinning of a lubricant significantly affects lubrication film generation at high shear rates. The critical shear rate, defined at the onset of shear thinning, marks the transition of lubricant behaviors. It is challenging to capture the entire shear-thinning curve by means of molecular dynamics (MD) simulations owing to the low signal-to-noise ratio or long calculation time at comparatively low shear rates (104-106 s-1), which is likely coincident with the shear rates of interest for lubrication applications. This paper proposes an approach that correlates the shear-thinning phenomenon with the change in the molecular conformation characterized by the radius of gyration of the molecule. Such a correlation should be feasible to capture the major mechanism of shear thinning for small- to moderate-sized non-spherical molecules, which is shear-induced molecular alignment. The idea is demonstrated by analyzing the critical shear rate for squalane (C30H62) and 1-decene trimer (C30H62); it is then implemented to study the behaviors of different molecular weight poly-α-olefin (PAO) structures. Time-temperature-pressure superpositioning (TTPS) is demonstrated and it helps further extend the ranges of the temperature and pressure for shear-thinning behavior analyses. The research leads to a relationship between molecular weight and critical shear rate for PAO structures, and the results are compared with those from the Einstein-Debye equation.

Moist and dry heating-induced changes in protein molecular structure, protein subfractions, and nutrient profiles in camelina seeds.

PubMed

Peng, Quanhui; Khan, Nazir A; Wang, Zhisheng; Yu, Peiqiang

2014-01-01

The objectives of the present study were to investigate the nutritive value of camelina seeds (Camelina sativa L. Crantz) in ruminant nutrition and to use molecular spectroscopy as a novel technique to quantify the heat-induced changes in protein molecular structures in relation to protein digestive behavior in the rumen and intestine of dairy cattle. In this study, camelina seeds were used as a model for feed protein. The seeds were kept as raw (control) or heated in an autoclave (moist heating) or in an air-draft oven (dry heating) at 120°C for 60 min. The parameters evaluated were (1) chemical profiles, (2) Cornell Net Protein and Carbohydrate System protein subfractions, (3) nutrient digestibilities and estimated energy values, (4) in situ rumen degradation and intestinal digestibility, and (5) protein molecular structures. Compared with raw seeds, moist heating markedly decreased (52.73 to 20.41%) the content of soluble protein and increased (2.00 to 9.01%) the content of neutral detergent insoluble protein in total crude protein (CP). Subsequently, the rapidly degradable Cornell Net Protein and Carbohydrate System CP fraction markedly decreased (45.06 to 16.69% CP), with a concomitant increase in the intermediately degradable (45.28 to 74.02% CP) and slowly degradable (1.13 to 8.02% CP) fractions, demonstrating a decrease in overall protein degradability in the rumen. The in situ rumen incubation study revealed that moist heating decreased (75.45 to 57.92%) rumen-degradable protein and increased (43.90 to 82.95%) intestinal digestibility of rumen-undegradable protein. The molecular spectroscopy study revealed that moist heating increased the amide I-to-amide II ratio and decreased α-helix and α-helix-to-β-sheet ratio. In contrast, dry heating did not significantly change CP solubility, rumen degradability, intestinal digestibility, and protein molecular structures compared with the raw seeds. Our results indicated that, compared with dry heating, moist heating markedly changed protein chemical profiles, protein subfractions, rumen protein degradability, and intestinal digestibility, which were associated with changes in protein molecular structures (amide I-to-amid II ratio and α-helix-to-β-sheet ratio). Moist heating improved the nutritive value and utilization of protein in camelina seeds compared with dry heating. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Molecular structure of self-assembled chiral nanoribbons and nanotubules revealed in the hydrated state.

PubMed

Oda, Reiko; Artzner, Franck; Laguerre, Michel; Huc, Ivan

2008-11-05

A detailed molecular organization of racemic 16-2-16 tartrate self-assembled multi-bilayer ribbons in the hydrated state is proposed where 16-2-16 amphiphiles, tartrate ions, and water molecules are all accurately positioned by comparing experimental X-ray powder diffraction and diffraction patterns derived from modeling studies. X-ray diffuse scattering studies show that molecular organization is not fundamentally altered when comparing the flat ribbons of the racemate to chirally twisted or helical ribbons of the pure tartrate enantiomer. Essential features of the three-dimensional molecular organizations of these structures include interdigitation of alkyl chains within each bilayer and well-defined networks of ionic and hydrogen bonds between cations, anions, and water molecules between bilayers. The detailed study of diffraction patterns also indicated that the gemini headgroups are oriented parallel to the long edge of the ribbons. The structure thus possesses a high cohesion and good crystallinity, and for the first time, we could relate the packing of the chiral molecules to the expression of the chirality at a mesoscopic scale. The organization of the ribbons at the molecular level sheds light on a number of their macroscopic features. Among these are the reason why enantiomerically pure 16-2-16 tartrate forms ribbons that consist of exactly two bilayers, and a plausible mechanism by which a chirally twisted or helical shape may emerge from the packing of chiral tartrate ions. Importantly, the distinction between commonly observed helical and twisted morphologies could be related to a subtle symmetry breaking. These results demonstrate that accurately solving the molecular structure of self-assembled soft materials--a process rarely achieved--is within reach, that it is a valid approach to correlate molecular parameters to macroscopic properties, and thus that it offers opportunities to modulate properties through molecular design.

Coupling of Molecular Emitters and Plasmonic Cavities beyond the Point-Dipole Approximation.

PubMed

Neuman, Tomáš; Esteban, Ruben; Casanova, David; García-Vidal, Francisco J; Aizpurua, Javier

2018-04-11

As the size of a molecular emitter becomes comparable to the dimensions of a nearby optical resonator, the standard approach that considers the emitter to be a point-like dipole breaks down. By adoption of a quantum description of the electronic transitions of organic molecular emitters, coupled to a plasmonic electromagnetic field, we are able to accurately calculate the position-dependent coupling strength between a plasmon and an emitter. The spatial distribution of excitonic and photonic quantum states is found to be a key aspect in determining the dynamics of molecular emission in ultrasmall cavities both in the weak and strong coupling regimes. Moreover, we show that the extreme localization of plasmonic fields leads to the selection rule breaking of molecular excitations.

Molecular understanding of osmosis in semipermeable membranes.

PubMed

Raghunathan, A V; Aluru, N R

2006-07-14

We investigate single-file osmosis of water through a semipermeable membrane with an uncharged, a positively and a negatively charged nanopore. Molecular dynamics simulations indicate that the osmotic flux through a negatively charged pore (J_) is higher compared to the osmotic flux in a positively charged pore (J+) followed by the osmotic flux in the uncharged pore (J(0)), i.e., J_ > J+ > J(0). The molecular mechanisms governing osmosis, steady state osmosis, and the observed osmotic flux dependence on the nanopore charge are explained by computing all the molecular interactions involved and identifying the molecular interactions that play an important role during and after osmosis. This study helps in a fundamental understanding of osmosis and in the design of advanced nanoporous membranes for various applications of osmosis.

Investigating the Fundamentals of Molecular Depth Profiling Using Strong-field Photoionization of Sputtered Neutrals

PubMed Central

Willingham, D.; Brenes, D. A.; Winograd, N.; Wucher, A.

2010-01-01

Molecular depth profiles of model organic thin films were performed using a 40 keV C60+ cluster ion source in concert with TOF-SIMS. Strong-field photoionization of intact neutral molecules sputtered by 40 keV C60+ primary ions was used to analyze changes in the chemical environment of the guanine thin films as a function of ion fluence. Direct comparison of the secondary ion and neutral components of the molecular depth profiles yields valuable information about chemical damage accumulation as well as changes in the molecular ionization probability. An analytical protocol based on the erosion dynamics model is developed and evaluated using guanine and trehalose molecular secondary ion signals with and without comparable laser photoionization data. PMID:26269660

INVESTIGATIONS INTO MOLECULAR PATHWAYS IN THE POST GENOME ERA: CROSS SPECIES COMPARATIVE GENOMICS APPROACH

EPA Science Inventory

Genome sequencing efforts in the past decade were aimed at generating draft sequences of many prokaryotic and eukaryotic model organisms. Successful completion of unicellular eukaryotes, worm, fly and human genome have opened up the new field of molecular biology and function...

78 FR 59040 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-25

..., [email protected] . Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated... Scientific Review Special Emphasis Panel, RFA Panel: Molecular Probes. Date: October 18, 2013. Time: 8:00 a.m... Assistance Program Nos. 93.306, Comparative Medicine; 93.333, Clinical Research, 93.306, 93.333, 93.337, 93...

76 FR 57066 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-15

... personal privacy. Name of Committee: Molecular, Cellular and Developmental Neuroscience Integrated Review, Group, Cellular and Molecular Biology of Glia Study Section. Date: October 14, 2011. Time: 8 a.m. to 7... Domestic Assistance Program Nos. 93.306, Comparative Medicine; 93.333, Clinical Research, 93.306, 93.333...

78 FR 53463 - Center for Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-29

...: Molecular, Cellular and Developmental Neuroscience Integrated Review Group; Neurotransporters, Receptors... Discovery and Molecular Pharmacology Study Section. Date: September 30, 2013. Time: 8:00 a.m. to 6:00 p.m....nih.gov . (Catalogue of Federal Domestic Assistance Program Nos. 93.306, Comparative Medicine; 93.333...

78 FR 72902 - Center For Scientific Review; Notice of Closed Meetings

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-04

... Panel Member Conflict: Molecular and Cellular Neurodegeneration. Date: January 6, 2014. Time: 1:00 p.m... for Scientific Review Special Emphasis Panel, Member Conflict: Molecular and Cellular Neurodevelopment....306, Comparative Medicine; 93.333, Clinical Research; 93.306, 93.333, 93.337, 93.393-93.396, 93.837-93...

Virulence Phenotypes and Molecular Genotypes of Puccinia triticina Isolates from Italy

USDA-ARS?s Scientific Manuscript database

Twenty-four isolates of Puccinia triticina from Italy were characterized for virulence to seedlings of 22 common wheat cv. Thatcher isolines each with a different leaf rust resistance gene, and for molecular genotypes at 15 simple sequence repeat (SSR) loci. The isolates were compared with a set of ...

Do Haptic Representations Help Complex Molecular Learning?

ERIC Educational Resources Information Center

Bivall, Petter; Ainsworth, Shaaron; Tibell, Lena A. E.

2011-01-01

This study explored whether adding a haptic interface (that provides users with somatosensory information about virtual objects by force and tactile feedback) to a three-dimensional (3D) chemical model enhanced students' understanding of complex molecular interactions. Two modes of the model were compared in a between-groups pre- and posttest…

Comparative transcriptome and lipidome analyses reveal molecular systems underlying chilling response in chilling-tolerant sorghums

USDA-ARS?s Scientific Manuscript database

Chilling temperatures are a major constraint for temperate cultivation of tropical-origin crops, including the cereal crop sorghum (Sorghum bicolor [L.] Moench). Northern Chinese sorghums have adapted to early-season chilling, but molecular mechanisms of chilling tolerance are unknown. We used RNA ...

Molecular Diagnosis of Chagas Disease in Colombia: Parasitic Loads and Discrete Typing Units in Patients from Acute and Chronic Phases

PubMed Central

Hernández, Carolina; Cucunubá, Zulma; Flórez, Carolina; Olivera, Mario; Valencia, Carlos; Zambrano, Pilar; León, Cielo; Ramírez, Juan David

2016-01-01

Background The diagnosis of Chagas disease is complex due to the dynamics of parasitemia in the clinical phases of the disease. The molecular tests have been considered promissory because they detect the parasite in all clinical phases. Trypanosoma cruzi presents significant genetic variability and is classified into six Discrete Typing Units TcI-TcVI (DTUs) with the emergence of foreseen genotypes within TcI as TcIDom and TcI Sylvatic. The objective of this study was to determine the operating characteristics of molecular tests (conventional and Real Time PCR) for the detection of T. cruzi DNA, parasitic loads and DTUs in a large cohort of Colombian patients from acute and chronic phases. Methodology/Principal Findings Samples were obtained from 708 patients in all clinical phases. Standard diagnosis (direct and serological tests) and molecular tests (conventional PCR and quantitative PCR) targeting the nuclear satellite DNA region. The genotyping was performed by PCR using the intergenic region of the mini-exon gene, the 24Sa, 18S and A10 regions. The operating capabilities showed that performance of qPCR was higher compared to cPCR. Likewise, the performance of qPCR was significantly higher in acute phase compared with chronic phase. The median parasitic loads detected were 4.69 and 1.33 parasite equivalents/mL for acute and chronic phases. The main DTU identified was TcI (74.2%). TcIDom genotype was significantly more frequent in chronic phase compared to acute phase (82.1% vs 16.6%). The median parasitic load for TcIDom was significantly higher compared with TcI Sylvatic in chronic phase (2.58 vs.0.75 parasite equivalents/ml). Conclusions/Significance The molecular tests are a precise tool to complement the standard diagnosis of Chagas disease, specifically in acute phase showing high discriminative power. However, it is necessary to improve the sensitivity of molecular tests in chronic phase. The frequency and parasitemia of TcIDom genotype in chronic patients highlight its possible relationship to the chronicity of the disease. PMID:27648938

Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis.

PubMed

Burr, Nick; Lummis, Katie; Sood, Ruchit; Kane, John Samuel; Corp, Aaron; Subramanian, Venkataraman

2017-02-01

Direct oral anticoagulants are increasingly used for a wide range of indications. However, data are conflicting about the risk of major gastrointestinal bleeding with these drugs. We compared the risk of gastrointestinal bleeding with direct oral anticoagulants, warfarin, and low-molecular-weight heparin. For this systematic review and meta-analysis, we searched MEDLINE and Embase from database inception to April 1, 2016, for prospective and retrospective studies that reported the risk of gastrointestinal bleeding with use of a direct oral anticoagulant compared with warfarin or low-molecular-weight heparin for all indications. We also searched the Cochrane Library for systematic reviews and assessment evaluations, the National Health Service (UK) Economic Evaluation Database, and ISI Web of Science for conference abstracts and proceedings (up to April 1, 2016). The primary outcome was the incidence of major gastrointestinal bleeding, with all gastrointestinal bleeding as a secondary outcome. We did a Bayesian network meta-analysis to produce incidence rate ratios (IRRs) with 95% credible intervals (CrIs). We identified 38 eligible articles, of which 31 were included in the primary analysis, including 287 692 patients exposed to 230 090 years of anticoagulant drugs. The risk of major gastrointestinal bleeding with direct oral anticoagulants did not differ from that with warfarin or low-molecular-weight heparin (factor Xa vs warfarin IRR 0·78 [95% CrI 0·47-1·08]; warfarin vs dabigatran 0·88 [0·59-1·36]; factor Xa vs low-molecular-weight heparin 1·02 [0·42-2·70]; and low-molecular-weight heparin vs dabigatran 0·67 [0·20-1·82]). In the secondary analysis, factor Xa inhibitors were associated with a reduced risk of all severities of gastrointestinal bleeding compared with warfarin (0·25 [0.07-0.76]) or dabigatran (0.24 [0.07-0.77]). Our findings show no increase in risk of major gastrointestinal bleeding with direct oral anticoagulants compared with warfarin or low-molecular-weight heparin. These findings support the continued use of direct oral anticoagulants. Leeds Teaching Hospitals Charitable Foundation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Double-hairpin molecular-beacon-based amplification detection for gene diagnosis linked to cancer.

PubMed

Xu, Huo; Zhang, Rongbo; Li, Feng; Zhou, Yingying; Peng, Ting; Wang, Xuedong; Shen, Zhifa

2016-09-01

A powerful double-hairpin molecular beacon (DHMB) was developed for cancer-related KRAS gene detection based on the one-to-two stoichiometry. During target DNA detection, DHMB can execute signal transduction even if no any exogenous element is involved. Unlike the conventional molecular beacon based on the one-to-one interaction, one target DNA not only hybridizes with one DHMB and opens its hairpin but also promotes the interaction between two DHMBs, causing the separation of two fluorophores from quenchers. This leads to an enhanced fluorescence signal. As a result, the target KRAS gene is able to be detected within a wide dynamic range from 0.05 to 200 nM with the detection limit of 50 pM, indicating a dramatic improvement compared with traditional molecular beacons. Moreover, the point mutations existing in target DNAs can be easily screened. The potential application for target species in real samples was indicated by the analysis of PCR amplicons of DNAs from the DNA extracted from SW620 cell. Besides becoming a promising candidate probe for molecular biology research and clinical diagnosis of genetic diseases, the DHMB is expected to provide a significant insight into the design of DNA probe-based homogenous sensing systems. Graphical Abstract A powerful double-hairpin molecular beacon (DHMB) was developed for cancer-related gene KRAS detection based on the one-to-two stoichiometry. Without the help of any exogenous probe, the point mutation is easily screened, and the target DNA can be quantified down to 50 pM, indicating a dramatic improvement compared with traditional molecular beacons.

Comparison of gravimetric and a double-indicator dilution technique for assessment of extra-vascular lung water in endotoxaemia.

PubMed

Rossi, P; Oldner, A; Wanecek, M; Leksell, L G; Rudehill, A; Konrad, D; Weitzberg, E

2003-03-01

To compare a molecular double-indicator dilution technique with the gravimetrical reference method for measurement of extra-vascular lung water in porcine endotoxin shock. Open comparative experimental study. Animal research laboratory. In fourteen anaesthetised, mechanically ventilated landrace pigs, central and pulmonary haemodynamics as well as pulmonary gas exchange were measured. Extra-vascular lung water was quantitated gravimetrically as well as with a molecular double indicator dilution technique. Eight of these animals were subjected to endotoxaemia, the rest serving as sham controls. No difference in extra-vascular lung water was observed between the two methods in sham animals. Furthermore, extra-vascular lung water assessed with the molecular double-indicator dilution technique at the initiation of endotoxin infusion did not differ significantly from the corresponding values for sham animals. Endotoxaemia induced a hypodynamic shock with concurrent pulmonary hypertension and a pronounced deterioration in gas exchange. No increase in extra-vascular lung water was detected with the molecular double-indicator dilution technique in response to endotoxin, whereas this parameter was significantly higher when assessed with the gravimetric method. The molecular double-indicator dilution technique showed similar results as the gravimetrical method for assessment of extra-vascular lung water in non-endotoxaemic conditions. However, during endotoxin-induced lung injury the molecular double indicator dilution technique failed to detect the significant increase in extra-vascular lung water as measured by the gravimetric method. These data suggest that the molecular double indicator dilution technique may be of limited value during sepsis-induced lung injury.

Molecular activity prediction by means of supervised subspace projection based ensembles of classifiers.

PubMed

Cerruela García, G; García-Pedrajas, N; Luque Ruiz, I; Gómez-Nieto, M Á

2018-03-01

This paper proposes a method for molecular activity prediction in QSAR studies using ensembles of classifiers constructed by means of two supervised subspace projection methods, namely nonparametric discriminant analysis (NDA) and hybrid discriminant analysis (HDA). We studied the performance of the proposed ensembles compared to classical ensemble methods using four molecular datasets and eight different models for the representation of the molecular structure. Using several measures and statistical tests for classifier comparison, we observe that our proposal improves the classification results with respect to classical ensemble methods. Therefore, we show that ensembles constructed using supervised subspace projections offer an effective way of creating classifiers in cheminformatics.

Conservative and dissipative force imaging of switchable rotaxanes with frequency-modulation atomic force microscopy

NASA Astrophysics Data System (ADS)

Farrell, Alan A.; Fukuma, Takeshi; Uchihashi, Takayuki; Kay, Euan R.; Bottari, Giovanni; Leigh, David A.; Yamada, Hirofumi; Jarvis, Suzanne P.

2005-09-01

We compare constant amplitude frequency modulation atomic force microscopy (FM-AFM) in ambient conditions to ultrahigh vacuum (UHV) experiments by analysis of thin films of rotaxane molecules. Working in ambient conditions is important for the development of real-world molecular devices. We show that the FM-AFM technique allows quantitative measurement of conservative and dissipative forces without instabilities caused by any native water layer. Molecular resolution is achieved despite the low Q-factor in the air. Furthermore, contrast in the energy dissipation is observed even at the molecular level. This should allow investigations into stimuli-induced sub-molecular motion of organic films.

Malaria Molecular Epidemiology: Lessons from the International Centers of Excellence for Malaria Research Network

PubMed Central

Escalante, Ananias A.; Ferreira, Marcelo U.; Vinetz, Joseph M.; Volkman, Sarah K.; Cui, Liwang; Gamboa, Dionicia; Krogstad, Donald J.; Barry, Alyssa E.; Carlton, Jane M.; van Eijk, Anna Maria; Pradhan, Khageswar; Mueller, Ivo; Greenhouse, Bryan; Andreina Pacheco, M.; Vallejo, Andres F.; Herrera, Socrates; Felger, Ingrid

2015-01-01

Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases. This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings. First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax. Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics. Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. PMID:26259945

Selection of molecular descriptors with artificial intelligence for the understanding of HIV-1 protease peptidomimetic inhibitors-activity.

PubMed

Sirois, S; Tsoukas, C M; Chou, Kuo-Chen; Wei, Dongqing; Boucher, C; Hatzakis, G E

2005-03-01

Quantitative Structure Activity Relationship (QSAR) techniques are used routinely by computational chemists in drug discovery and development to analyze datasets of compounds. Quantitative numerical methods like Partial Least Squares (PLS) and Artificial Neural Networks (ANN) have been used on QSAR to establish correlations between molecular properties and bioactivity. However, ANN may be advantageous over PLS because it considers the interrelations of the modeled variables. This study focused on the HIV-1 Protease (HIV-1 Pr) inhibitors belonging to the peptidomimetic class of compounds. The main objective was to select molecular descriptors with the best predictive value for antiviral potency (Ki). PLS and ANN were used to predict Ki activity of HIV-1 Pr inhibitors and the results were compared. To address the issue of dimensionality reduction, Genetic Algorithms (GA) were used for variable selection and their performance was compared against that of ANN. Finally, the structure of the optimum ANN achieving the highest Pearson's-R coefficient was determined. On the basis of Pearson's-R, PLS and ANN were compared to determine which exhibits maximum performance. Training and validation of models was performed on 15 random split sets of the master dataset consisted of 231 compounds. For each compound 192 molecular descriptors were considered. The molecular structure and constant of inhibition (Ki) were selected from the NIAID database. Study findings suggested that non-covalent interactions such as hydrophobicity, shape and hydrogen bonding describe well the antiviral activity of the HIV-1 Pr compounds. The significance of lipophilicity and relationship to HIV-1 associated hyperlipidemia and lipodystrophy syndrome warrant further investigation.

Water cavities of sH clathrate hydrate stabilized by molecular hydrogen.

PubMed

Strobel, Timothy A; Koh, Carolyn A; Sloan, E Dendy

2008-02-21

X-ray diffraction and Raman spectroscopic measurements confirm that molecular hydrogen can be contained within the small water cavities of a binary sH clathrate hydrate using large guest molecules that stabilize the large cavity. The potential increase in hydrogen storage could be more than 40% when compared with binary sII hydrates. This work demonstrates the stabilization of hydrogen in a hydrate structure previously unknown for encapsulating molecular hydrogen, indicating the potential for other inclusion compound materials with even greater hydrogen storage capabilities.

Equilibrium Structures and Absorption Spectra for SixOy-nH2O Molecular Clusters using Density Functional Theory

DTIC Science & Technology

2017-05-04

Naval Research Laboratory Washington, DC 20375-5320 NRL/MR/6390--17-9723 Equilibrium Structures and Absorption Spectra for SixOy-nH2O Molecular...Absorption Spectra for SixOy-nH2O Molecular Clusters using Density Functional Theory L. Huang, S.G. Lambrakos, and L. Massa1 Naval Research Laboratory, Code...and time-dependent density functional theory (TD-DFT). The size of the clusters considered is relatively large compared to those considered in

Overlapping molecular pathological themes link Charcot-Marie-Tooth neuropathies and hereditary spastic paraplegias.

PubMed

Timmerman, Vincent; Clowes, Virginia E; Reid, Evan

2013-08-01

In this review we focus on Charcot-Marie-Tooth (CMT) neuropathies and hereditary spastic paraplegias (HSPs). Although these diseases differ in whether they primarily affect the peripheral or central nervous system, both are genetically determined, progressive, long axonopathies that affect motor and sensory pathways. This commonality suggests that there might be similarities in the molecular pathology underlying these conditions, and here we compare the molecular genetics and cellular pathology of the two groups. Copyright © 2012 Elsevier Inc. All rights reserved.

A molecular dynamics study of polymer/graphene interfacial systems

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rissanou, Anastassia N.; Harmandaris, Vagelis

2014-05-15

Graphene based polymer nanocomposites are hybrid materials with a very broad range of technological applications. In this work, we study three hybrid polymer/graphene interfacial systems (polystyrene/graphene, poly(methyl methacrylate)/graphene and polyethylene/graphene) through detailed atomistic molecular dynamics (MD) simulations. Density profiles, structural characteristics and mobility aspects are being examined at the molecular level for all model systems. In addition, we compare the properties of the hybrid systems to the properties of the corresponding bulk ones, as well as to theoretical predictions.

Generation and detection of the cyclohexadienyl radical in phosphonium ionic liquids.

PubMed

Lauzon, J M; Arseneau, D J; Brodovitch, J C; Clyburne, J A C; Cormier, P; McCollum, B; Ghandi, K

2008-10-21

The formation of the cyclohexadienyl radical, C(6)H(6)Mu, in ionic and molecular solvents has been compared. This is the first time that a muoniated free radical is reported in an ionic liquid. In marked contrast to molecular liquids, free radical generation in ionic liquids is significantly enhanced. Comparison of the hyperfine interactions in the ionic liquid and in molecular solvents and with theoretical calculations, suggests significant and unforeseen solvent interaction with the cyclohexadienyl radical.

Why human milk is more nutritious than cow milk

NASA Astrophysics Data System (ADS)

Voorhoeve, Niels; Allan, Douglas C.; Moret, M. A.; Zebende, G. F.; Phillips, J. C.

2018-05-01

The evolution of milk, the key infant nutrient, is analyzed using a novel thermodynamic molecular method. The method is general, and it has many advantages compared to conventional molecular dynamics simulations. It is much simpler, and it connects amino acid sequences directly to function, often without knowing detailed "folded" globular structures. It emphasizes synchronized critical fluctuations due to long-range correlations in globular curvatures. The titled question has not been answered, or even discussed successfully, by other molecular methods.

Performance evaluation of integrating detectors for near-infrared fluorescence molecular imaging

NASA Astrophysics Data System (ADS)

Zhu, Banghe; Rasmussen, John C.; Sevick-Muraca, Eva M.

2014-05-01

Although there has been a plethora of devices advanced for clinical translation, there has been no standards to compare and determine the optical device for fluorescence molecular imaging. In this work, we compare different CCD configurations using a solid phantom developed to mimic pM - fM concentrations of near-infrared fluorescent dyes in tissues. Our results show that intensified CCD systems (ICCDs) offer greater contrast at larger signal-tonoise ratios (SNRs) in comparison to their un-intensified CCD systems operated at clinically reasonable, sub-second acquisition times. Furthermore, we compared our investigational ICCD device to the commercial NOVADAQ SPY system, demonstrating different performance in both SNR and contrast.

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.

PubMed

Tammimies, Kristiina; Marshall, Christian R; Walker, Susan; Kaur, Gaganjot; Thiruvahindrapuram, Bhooma; Lionel, Anath C; Yuen, Ryan K C; Uddin, Mohammed; Roberts, Wendy; Weksberg, Rosanna; Woodbury-Smith, Marc; Zwaigenbaum, Lonnie; Anagnostou, Evdokia; Wang, Zhuozhi; Wei, John; Howe, Jennifer L; Gazzellone, Matthew J; Lau, Lynette; Sung, Wilson W L; Whitten, Kathy; Vardy, Cathy; Crosbie, Victoria; Tsang, Brian; D'Abate, Lia; Tong, Winnie W L; Luscombe, Sandra; Doyle, Tyna; Carter, Melissa T; Szatmari, Peter; Stuckless, Susan; Merico, Daniele; Stavropoulos, Dimitri J; Scherer, Stephen W; Fernandez, Bridget A

2015-09-01

The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study. To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic. The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6). All probands underwent CMA, with WES performed for 95 proband-parent trios. The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups. Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text]. Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.

Molecular implementation of simple logic programs.

PubMed

Ran, Tom; Kaplan, Shai; Shapiro, Ehud

2009-10-01

Autonomous programmable computing devices made of biomolecules could interact with a biological environment and be used in future biological and medical applications. Biomolecular implementations of finite automata and logic gates have already been developed. Here, we report an autonomous programmable molecular system based on the manipulation of DNA strands that is capable of performing simple logical deductions. Using molecular representations of facts such as Man(Socrates) and rules such as Mortal(X) <-- Man(X) (Every Man is Mortal), the system can answer molecular queries such as Mortal(Socrates)? (Is Socrates Mortal?) and Mortal(X)? (Who is Mortal?). This biomolecular computing system compares favourably with previous approaches in terms of expressive power, performance and precision. A compiler translates facts, rules and queries into their molecular representations and subsequently operates a robotic system that assembles the logical deductions and delivers the result. This prototype is the first simple programming language with a molecular-scale implementation.

Vibrational, spectroscopic, molecular docking and density functional theory studies on N-(5-aminopyridin-2-yl)acetamide

NASA Astrophysics Data System (ADS)

Asath, R. Mohamed; Rekha, T. N.; Premkumar, S.; Mathavan, T.; Benial, A. Milton Franklin

2016-12-01

Conformational analysis was carried out for N-(5-aminopyridin-2-yl)acetamide (APA) molecule. The most stable, optimized structure was predicted by the density functional theory calculations using the B3LYP functional with cc-pVQZ basis set. The optimized structural parameters and vibrational frequencies were calculated. The experimental and theoretical vibrational frequencies were assigned and compared. Ultraviolet-visible spectrum was simulated and validated experimentally. The molecular electrostatic potential surface was simulated. Frontier molecular orbitals and related molecular properties were computed, which reveals that the higher molecular reactivity and stability of the APA molecule and further density of states spectrum was simulated. The natural bond orbital analysis was also performed to confirm the bioactivity of the APA molecule. Antidiabetic activity was studied based on the molecular docking analysis and the APA molecule was identified that it can act as a good inhibitor against diabetic nephropathy.

Studies on molecular structure, vibrational spectra and molecular docking analysis of 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate

NASA Astrophysics Data System (ADS)

Suresh, D. M.; Amalanathan, M.; Hubert Joe, I.; Bena Jothy, V.; Diao, Yun-Peng

2014-09-01

The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule.

Molecular dynamics simulations of classical sound absorption in a monatomic gas

NASA Astrophysics Data System (ADS)

Ayub, M.; Zander, A. C.; Huang, D. M.; Cazzolato, B. S.; Howard, C. Q.

2018-05-01

Sound wave propagation in argon gas is simulated using molecular dynamics (MD) in order to determine the attenuation of acoustic energy due to classical (viscous and thermal) losses at high frequencies. In addition, a method is described to estimate attenuation of acoustic energy using the thermodynamic concept of exergy. The results are compared against standing wave theory and the predictions of the theory of continuum mechanics. Acoustic energy losses are studied by evaluating various attenuation parameters and by comparing the changes in behavior at three different frequencies. This study demonstrates acoustic absorption effects in a gas simulated in a thermostatted molecular simulation and quantifies the classical losses in terms of the sound attenuation constant. The approach can be extended to further understanding of acoustic loss mechanisms in the presence of nanoscale porous materials in the simulation domain.

Molecular Velcro constructed from polymer loop brushes showing enhanced adhesion force

NASA Astrophysics Data System (ADS)

Zhou, Tian; Han, Biao; Han, Lin; Li, Christopher; Department of Materials Science; Engineering Team; School of Biomedical Engineering, Science; Health Systems Team

2015-03-01

Molecular Velcro is commonly seen in biological systems as the formation of strong physical entanglement at molecular scale could induce strong adhesion, which is crucial to many biological processes. To mimic this structure, we designed, and fabricated polymer loop brushes using polymer single crystals with desired surface functionality and controlled chain folding. Compared with reported loop brushes fabricated using triblock copolymers, the present loop bushes have precise loop sizes, loop grafting density, and well controlled tethering locations on the solid surface. Atomic force microscopy-based force spectroscopy measurements using a polymer chain coated probe reveal that the adhesion force are significantly enhanced on the loop brush surface as compared with its single-strand counterpart. This study directly shows the effect of polymer brush conformation on their properties, and suggests a promising strategy for advanced polymer surface design.

A Force Balanced Fragmentation Method for ab Initio Molecular Dynamic Simulation of Protein.

PubMed

Xu, Mingyuan; Zhu, Tong; Zhang, John Z H

2018-01-01

A force balanced generalized molecular fractionation with conjugate caps (FB-GMFCC) method is proposed for ab initio molecular dynamic simulation of proteins. In this approach, the energy of the protein is computed by a linear combination of the QM energies of individual residues and molecular fragments that account for the two-body interaction of hydrogen bond between backbone peptides. The atomic forces on the caped H atoms were corrected to conserve the total force of the protein. Using this approach, ab initio molecular dynamic simulation of an Ace-(ALA) 9 -NME linear peptide showed the conservation of the total energy of the system throughout the simulation. Further a more robust 110 ps ab initio molecular dynamic simulation was performed for a protein with 56 residues and 862 atoms in explicit water. Compared with the classical force field, the ab initio molecular dynamic simulations gave better description of the geometry of peptide bonds. Although further development is still needed, the current approach is highly efficient, trivially parallel, and can be applied to ab initio molecular dynamic simulation study of large proteins.

Gas production in the radiolysis of Poly(dimethysiloxanes)

NASA Astrophysics Data System (ADS)

LaVerne, Jay A.; Tratnik, Nicole A. I.; Sasgen, Andrea

2018-01-01

A variety of small poly(dimethyl siloxanes) were irradiated with γ-rays followed by the determination of the production of methane and molecular hydrogen and characterization of spectroscopic changes in the medium. The yields of methane was found to be about twice that of molecular hydrogen indicating that breakage of the C-Si bond occurs at a frequency comparable to the breakage of the C-H bond. Both yields slowly decrease with increasing molecular weight of the medium. The presence of oxygen decreases the yield of both gases suggesting radical precursors to methane and molecular hydrogen, presumably the methyl radical and H atom, respectively. Temperature gravimetric analysis and UV-visible spectroscopy both suggest the formation of higher molecular weight compounds with radiolysis, which agrees with bond loss and formation observed in infrared spectroscopy.

Molecular hyperfine fields in organic magnetoresistance devices

NASA Astrophysics Data System (ADS)

Giro, Ronaldo; Rosselli, Flávia P.; dos Santos Carvalho, Rafael; Capaz, Rodrigo B.; Cremona, Marco; Achete, Carlos A.

2013-03-01

We calculate molecular hyperfine fields in organic magnetoresistance (OMAR) devices using ab initio calculations. To do so, we establish a protocol for the accurate determination of the average hyperfine field Bhf and apply it to selected molecular ions: NPB, TPD, and Alq3. Then, we make devices with precisely the same molecules and perform measurements of the OMAR effect, in order to address the role of hole-transport layer in the characteristic magnetic field B0 of OMAR. Contrary to common belief, we find that molecular hyperfine fields are not only caused by hydrogen nuclei. We also find that dipolar contributions to the hyperfine fields can be comparable to the Fermi contact contributions. However, such contributions are restricted to nuclei located in the same molecular ion as the charge carrier (intramolecular), as extramolecular contributions are negligible.

The JCMT nearby galaxies legacy survey - X. Environmental effects on the molecular gas and star formation properties of spiral galaxies

NASA Astrophysics Data System (ADS)

Mok, Angus; Wilson, C. D.; Golding, J.; Warren, B. E.; Israel, F. P.; Serjeant, S.; Knapen, J. H.; Sánchez-Gallego, J. R.; Barmby, P.; Bendo, G. J.; Rosolowsky, E.; van der Werf, P.

2016-03-01

We present a study of the molecular gas properties in a sample of 98 H I - flux selected spiral galaxies within ˜25 Mpc, using the CO J = 3 - 2 line observed with the James Clerk Maxwell Telescope. We use the technique of survival analysis to incorporate galaxies with CO upper limits into our results. Comparing the group and Virgo samples, we find a larger mean H2 mass in the Virgo galaxies, despite their lower mean H I mass. This leads to a significantly higher H2 to H I ratio for Virgo galaxies. Combining our data with complementary Hα star formation rate measurements, Virgo galaxies have longer molecular gas depletion times compared to group galaxies, due to their higher H2 masses and lower star formation rates. We suggest that the longer depletion times may be a result of heating processes in the cluster environment or differences in the turbulent pressure. From the full sample, we find that the molecular gas depletion time has a positive correlation with the stellar mass, indicative of differences in the star formation process between low- and high-mass galaxies, and a negative correlation between the molecular gas depletion time and the specific star formation rate.

Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

PubMed Central

Lequerré, Thierry; Bansard, Carine; Vittecoq, Olivier; Derambure, Céline; Hiron, Martine; Daveau, Maryvonne; Tron, François; Ayral, Xavier; Biga, Norman; Auquit-Auckbur, Isabelle; Chiocchia, Gilles; Le Loët, Xavier; Salier, Jean-Philippe

2009-01-01

Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment. PMID:19563633

Synthesis of High Molecular Weight Poly(glycerol monomethacrylate) via RAFT Emulsion Polymerization of Isopropylideneglycerol Methacrylate

PubMed Central

2018-01-01

High molecular weight water-soluble polymers are widely used as flocculants or thickeners. However, synthesis of such polymers via solution polymerization invariably results in highly viscous fluids, which makes subsequent processing somewhat problematic. Alternatively, such polymers can be prepared as colloidal dispersions; in principle, this is advantageous because the particulate nature of the polymer chains ensures a much lower fluid viscosity. Herein we exemplify the latter approach by reporting the convenient one-pot synthesis of high molecular weight poly(glycerol monomethacrylate) (PGMA) via the reversible addition–fragmentation chain transfer (RAFT) aqueous emulsion polymerization of a water-immiscible protected monomer precursor, isopropylideneglycerol methacrylate (IPGMA) at 70 °C, using a water-soluble poly(glycerol monomethacrylate) (PGMA) chain transfer agent as a steric stabilizer. This formulation produces a low-viscosity aqueous dispersion of PGMA–PIPGMA diblock copolymer nanoparticles at 20% solids. Subsequent acid deprotection of the hydrophobic core-forming PIPGMA block leads to particle dissolution and affords a viscous aqueous solution comprising high molecular weight PGMA homopolymer chains with a relatively narrow molecular weight distribution. Moreover, it is shown that this latex precursor route offers an important advantage compared to the RAFT aqueous solution polymerization of glycerol monomethacrylate since it provides a significantly faster rate of polymerization (and hence higher monomer conversion) under comparable conditions. PMID:29805184

Surface segregation and surface tension of polydisperse polymer melts.

PubMed

Minnikanti, Venkatachala S; Qian, Zhenyu; Archer, Lynden A

2007-04-14

The effect of polydispersity on surface segregation of a lower molecular weight polymer component in a higher molecular weight linear polymer melt host is investigated theoretically. We show that the integrated surface excess zM of a polymer component of molecular weight M satisfies a simple relation zM=2Ue(M/Mw-1)phiM, where Mw is the weight averaged molecular weight, phiM is the polymer volume fraction, and Ue is the attraction of polymer chain ends to the surface. Ue is principally of entropic origin, but also reflects any energetic preference of chain ends to the surface. We further show that the surface tension gammaM of a polydisperse melt of high molar mass components depends on the number average degree of polymerization Mn as, gammaM=gammainfinity+2UerhobRT/Mn. The parameter gammainfinity is the asymptotic surface tension of an infinitely long polymer of the same chemistry, rhob is the bulk density of the polymer, R is the universal gas constant, and T is the temperature. The predicted gammaM compare favorably with surface tension values obtained from self-consistent field theory simulations that include equation of state effects, which account for changes in polymer density with molecular weight. We also compare the predicted surface tension with available experimental data.

Preparation of l-phenylalanine-imprinted solid-phase extraction sorbent by Pickering emulsion polymerization and the selective enrichment of l-phenylalanine from human urine.

PubMed

Li, Ji; Hu, Xiaoling; Guan, Ping; Zhang, Xiaoyan; Qian, Liwei; Zhang, Nan; Du, Chunbao; Song, Renyuan

2016-05-01

A novel l-phenylalanine molecularly imprinted solid-phase extraction sorbent was synthesized by the combination of Pickering emulsion polymerization and ion-pair dummy template imprinting. Compared to other polymerization methods, the molecularly imprinted polymers thus prepared exhibit a high specific surface, large pore diameter, and appropriate particle size. The key parameters for solid-phase extraction were optimized, and the result indicated that the molecularly imprinted polymer thus prepared exhibits a good recovery of 98.9% for l-phenylalanine. Under the optimized conditions of the procedure, an analytical method for l-phenylalanine was well established. By comparing the performance of the molecularly imprinted polymer and a commercial reverse-phase silica gel, the obtained molecularly imprinted polymer as an solid-phase extraction sorbent is more suitable, exhibiting high precision (relative standard deviation 3.2%, n = 4) and a low limit of detection (60.0 ± 1.9 nmol·L(-1) ) for the isolation of l-phenylalanine. Based on these results, the combination of the Pickering emulsion polymerization and ion-pair dummy template imprinting is effective for preparing selective solid-phase extraction sorbents for the separation of amino acids and organic acids from complex biological samples. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[Comparison study on adsorption of middle molecular substances with multiwalled carbon nanotubes and activated carbon].

PubMed

Li, Guifeng; Wan, Jianxin; Huang, Xiangqian; Zeng, Qiao; Tang, Jing

2011-08-01

In recent years, multi-walled carbon nanotubes (MWCTs) are very favorable to the adsorption of middle molecular substances in the hemoperfusion because of their multiporous structure, large surface area and high reactivity, which are beneficial to the excellent absorption properties. The purpose of this study was to study the MWCTs on the adsorption capacity of the middle molecular substances. Vitamin B12 (VB12) was selected as a model of the middle molecular substances. The morphologies of MWCTs and activated carbon from commercial "carbon kidney" were observed with scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The adsorption behavior of VB12 was compared to each other with UV-visible absorption spectra. The MWCTs formed a sophistaicate gap structure, and compared to the activated carbon, MWCTs had a larger surface area. By Langmuir equation and Freundlich equation fitting analysis, VB12 adsorption on MWCTs is fit for multi-molecular layer adsorption, and the adsorption type of activated carbon is more inclined to the model corresponding to Langmuir monolayer adsorption. The adsorption rate of MWCTs is faster than that of the activated carbon and the adsorption capacity is greater, which could be expected to become the new adsorbent in the hemoperfusion.

Molecular simulation of disjoining-pressure isotherms for free liquid , Lennard-Jones thin films

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bhatt, Divesh; Newman, John; Radke, C.J.

2001-10-01

We present canonical-ensemble molecular-dynamics simulations of disjoining-pressure isotherms in Lennard-Jones free liquid films. Thermodynamics demands that the disjoining pressure is determined uniquely as a function of the chemical potential purely from the phase diagram of the fluid. Our results from molecular dynamics validate this argument. The inverse-sixth-power distance term in the Lennard-Jones intermolecular potential represents van der Waals dispersion forces. Hence, we compare our results with classical Hamaker theory that is based on dispersion forces but assumes a slab geometry for the density profile and completely neglects fluid structure and entropy. We find that the Hamaker constant obtained from ourmore » simulations is about an order of magnitude larger than that from classical theory. To investigate the origin of this discrepancy, we calculate the disjoining-pressure isotherm using a density-functional theory relaxing the inherent assumptions in the Hamaker theory and imparting to the fluid an approximate structure. For disjoining pressure as a function of chemical potential, the results of density-functional theory and molecular dynamics are very close. Even for disjoining-pressure isotherms, and the subsequently calculated Hamaker constant, results of the density-functional theory are closer to the molecular-dynamics simulations by about a factor of 4 compared to Hamaker theory. [References: 44]« less

Unexpected diversity of Anopheles species in Eastern Zambia: implications for evaluating vector behavior and interventions using molecular tools.

PubMed

Lobo, Neil F; St Laurent, Brandyce; Sikaala, Chadwick H; Hamainza, Busiku; Chanda, Javan; Chinula, Dingani; Krishnankutty, Sindhu M; Mueller, Jonathan D; Deason, Nicholas A; Hoang, Quynh T; Boldt, Heather L; Thumloup, Julie; Stevenson, Jennifer; Seyoum, Aklilu; Collins, Frank H

2015-12-09

The understanding of malaria vector species in association with their bionomic traits is vital for targeting malaria interventions and measuring effectiveness. Many entomological studies rely on morphological identification of mosquitoes, limiting recognition to visually distinct species/species groups. Anopheles species assignments based on ribosomal DNA ITS2 and mitochondrial DNA COI were compared to morphological identifications from Luangwa and Nyimba districts in Zambia. The comparison of morphological and molecular identifications determined that interpretations of species compositions, insecticide resistance assays, host preference studies, trap efficacy, and Plasmodium infections were incorrect when using morphological identification alone. Morphological identifications recognized eight Anopheles species while 18 distinct sequence groups or species were identified from molecular analyses. Of these 18, seven could not be identified through comparison to published sequences. Twelve of 18 molecularly identified species (including unidentifiable species and species not thought to be vectors) were found by PCR to carry Plasmodium sporozoites - compared to four of eight morphological species. Up to 15% of morphologically identified Anopheles funestus mosquitoes in insecticide resistance tests were found to be other species molecularly. The comprehension of primary and secondary malaria vectors and bionomic characteristics that impact malaria transmission and intervention effectiveness are fundamental in achieving malaria elimination.

A Comparison of Two Methods of Teaching Molecular Architecture to High School Chemistry Students.

ERIC Educational Resources Information Center

Halsted, Douglas Alan

This investigation explored the question of how high school chemistry students best learn three-dimensional molecular, ionic, and metallic structures in CHEM Study (Freeman, 1963). The experimenter compared the achievement, attitude, and instructional preferences of 110 randomly selected students taught by two different methods: (1) student…

Molecular Orbitals of NO, NO[superscript+], and NO[superscript-]: A Computational Quantum Chemistry Experiment

ERIC Educational Resources Information Center

Orenha, Renato P.; Galembeck, Sérgio E.

2014-01-01

This computational experiment presents qualitative molecular orbital (QMO) and computational quantum chemistry exercises of NO, NO[superscript+], and NO[superscript-]. Initially students explore several properties of the target molecules by Lewis diagrams and the QMO theory. Then, they compare qualitative conclusions with EHT and DFT calculations…

A new insight of the northern filaments of Centaurus A

NASA Astrophysics Data System (ADS)

Salomé, Q.; Salomé, P.; Combes, F.; Hamer, S.

2016-12-01

We present new APEX observations of the CO(2-1) in the northern filaments of Centaurus A, at the intersection between the radio jet and the northern H num{1} shell. The CO emission was compared with archival FUV (GALEX), FIR (Herschel) and VLT/MUSE data. The molecular gas mass of the filaments is (8.2± 0.5)× 10^7: M_⊙, distributed in two filamentary structures. We found a surprisingly strong molecular filament that lies outside the H num{1} gas. The filaments are mostly molecular, suggesting a scenario where the radio-jet triggers the atomic-to-molecular phase transition. We then compared the CO masses with the SFR estimates and found very long depletion times (˜ 75: Gyr over the whole filaments), in agreement with the results of te{SalomeQ_2016}. Analysis of optical excitation lines indicates that the filaments are mostly excited by the AGN or shocks. Comparison with the Hα and H num{1} emission suggests that the three gas phases are spatially and kinematically linked. In particular, the CO emission shows the same velocity gradient as the H num{1} gas.

Scalable and fast heterogeneous molecular simulation with predictive parallelization schemes

NASA Astrophysics Data System (ADS)

Guzman, Horacio V.; Junghans, Christoph; Kremer, Kurt; Stuehn, Torsten

2017-11-01

Multiscale and inhomogeneous molecular systems are challenging topics in the field of molecular simulation. In particular, modeling biological systems in the context of multiscale simulations and exploring material properties are driving a permanent development of new simulation methods and optimization algorithms. In computational terms, those methods require parallelization schemes that make a productive use of computational resources for each simulation and from its genesis. Here, we introduce the heterogeneous domain decomposition approach, which is a combination of an heterogeneity-sensitive spatial domain decomposition with an a priori rearrangement of subdomain walls. Within this approach, the theoretical modeling and scaling laws for the force computation time are proposed and studied as a function of the number of particles and the spatial resolution ratio. We also show the new approach capabilities, by comparing it to both static domain decomposition algorithms and dynamic load-balancing schemes. Specifically, two representative molecular systems have been simulated and compared to the heterogeneous domain decomposition proposed in this work. These two systems comprise an adaptive resolution simulation of a biomolecule solvated in water and a phase-separated binary Lennard-Jones fluid.

[Levels and molecular heterogeneity of serotonin transporter protein in platelets of patients with different mental diseases: a comparative analysis with the use of monoclonal and polyclonal antibodies].

PubMed

Brusov, O S; Faktor, M I; Zlobina, G P; Bologov, P V; Kaleda, V G; Oleĭchik, I V; Korenev, A N; Piatnitskiĭ, A N; Dupin, A M; Katasonov, A B; Morozova, M A; Beniashvili, A G; Lozier, R Kh; Pavlova, E V; Segal, O L; Massino, Iu S; Dmitriev, A D

2001-01-01

Polyclonal (PAb) and monoclonal (MAb) antibodies to CT2-epitope of the C-terminal fragment of serotonin transporter (SERT) protein were used to study the levels and molecular heterogeneity of platelet SERT in healthy donors and patients with affective (AD) and somatoform (SD) disorders, schizoaffective disorder (SAD) and schizophrenia. SERT was found to exist as high molecular wight (HMW) and low molecular weight (LMW) forms separated after electrophoresis. The levels of HMW and LMW forms of SERT were significantly, decreased in mentally ill patients as compared to healthy individuals. Unlike PAb, horse radish peroxidase (HRP)-conjugated MAbs were more sensitive and specific to SERT and could detect the LMW form of SERT as a duplet protein form with MW about 40 and 43 kDa. The MAb to CT2 C-terminal fragment of SERT conjugated with HRP is considered to be a new valuable tool for further investigation of SERT expression, properties, and posttranslation modification in the controls and in patients with different psychopathology.

Molecular Characterization of Transgenic Events Using Next Generation Sequencing Approach.

PubMed

Guttikonda, Satish K; Marri, Pradeep; Mammadov, Jafar; Ye, Liang; Soe, Khaing; Richey, Kimberly; Cruse, James; Zhuang, Meibao; Gao, Zhifang; Evans, Clive; Rounsley, Steve; Kumpatla, Siva P

2016-01-01

Demand for the commercial use of genetically modified (GM) crops has been increasing in light of the projected growth of world population to nine billion by 2050. A prerequisite of paramount importance for regulatory submissions is the rigorous safety assessment of GM crops. One of the components of safety assessment is molecular characterization at DNA level which helps to determine the copy number, integrity and stability of a transgene; characterize the integration site within a host genome; and confirm the absence of vector DNA. Historically, molecular characterization has been carried out using Southern blot analysis coupled with Sanger sequencing. While this is a robust approach to characterize the transgenic crops, it is both time- and resource-consuming. The emergence of next-generation sequencing (NGS) technologies has provided highly sensitive and cost- and labor-effective alternative for molecular characterization compared to traditional Southern blot analysis. Herein, we have demonstrated the successful application of both whole genome sequencing and target capture sequencing approaches for the characterization of single and stacked transgenic events and compared the results and inferences with traditional method with respect to key criteria required for regulatory submissions.

A molecular signaling approach to linking intraspecific variation and macro-evolutionary patterns.

PubMed

Swanson, Eli M; Snell-Rood, Emilie C

2014-11-01

Macro-evolutionary comparisons are a valued tool in evolutionary biology. Nevertheless, our understanding of how systems involved in molecular signaling change in concert with phenotypic diversification has lagged. We argue that integrating our understanding of the evolution of molecular signaling systems with phylogenetic comparative methods is an important step toward understanding the processes linking variation among individuals with variation among species. Focusing mostly on the endocrine system, we discuss how the complexity and mechanistic nature of molecular signaling systems may influence the application and interpretation of macro-evolutionary comparisons. We also detail five hypotheses concerning the role that physiological mechanisms can play in shaping macro-evolutionary patterns, and discuss ways in which these hypotheses could influence phenotypic diversification. Finally, we review a series of tools able to analyze the complexity of physiological systems and the way they change in concert with the phenotypes for which they coordinate development. © The Author 2014. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved. For permissions please email: journals.permissions@oup.com.

Exploring the binding mechanism of Heteroaryldihydropyrimidines and Hepatitis B Virus capsid combined 3D-QSAR and molecular dynamics.

PubMed

Tu, Jing; Li, Jiao Jiao; Shan, Zhi Jie; Zhai, Hong Lin

2017-01-01

The non-nucleoside drugs have been developed to treat HBV infection owing to their increased efficacy and lesser side effects, in which heteroaryldihydropyrimidines (HAPs) have been identified as effective inhibitors of HBV capsid. In this paper, the binding mechanism of HAPs targeting on HBV capsid protein was explored through three-dimensional quantitative structure-activity relationship, molecular dynamics and binding free energy decompositions. The obtained models of comparative molecular field analysis and comparative molecular similarity indices analysis enable the sufficient interpretation of structure-activity relationship of HAPs-HBV. The binding free energy analysis correlates with the experimental data. The computational results disclose that the non-polar contribution is the major driving force and Y132A mutation enhances the binding affinity for inhibitor 2 bound to HBV. The hydrogen bond interactions between the inhibitors and Trp102 help to stabilize the conformation of HAPs-HBV. The study provides insight into the binding mechanism of HAPs-HBV and would be useful for the rational design and modification of new lead compounds of HAP drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Gastric Cancer Cells in Peritoneal Lavage Fluid: A Systematic Review Comparing Cytological with Molecular Detection for Diagnosis of Peritoneal Metastases and Prediction of Peritoneal Recurrences.

PubMed

Virgilio, Edoardo; Giarnieri, Enrico; Giovagnoli, Maria Rosaria; Montagnini, Monica; Proietti, Antonella; D'Urso, Rosaria; Mercantini, Paolo; Valabrega, Stefano; Balducci, Genoveffa; Cavallini, Marco

2018-03-01

Detecting free tumor cells in the peritoneal lavage fluid of gastric cancer patients permits to assess a more accurate prognosis, predict peritoneal recurrence and select cases for a more aggressive treatment. Currently, cytology and molecular biology comprise the two most popular methods of detection that are under constant study by researchers. We burrowed into the available literature comparing cytological with molecular detection of free intraperitoneal gastric cancer cells. PubMed, Science Direct, Scopus and Google Scholar were the search engines investigated. As of 2017, 51 dedicated studies have been published. Messenger RNA of carcinoembryonic antigen was the genetic target most frequently described. The genetic technique is usually superior to cytology in sensitivity (38-100% vs. 12.3-67% respectively), whereas cytological examination tends to show a slight pre-eminence in specificity (approximately 100%). So far, given the imperfection of each method, employment of both cytology and molecular examination seem to be mandatory. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Live Cell Imaging of Viscosity in 3D Tumour Cell Models.

PubMed

Shirmanova, Marina V; Shimolina, Lubov' E; Lukina, Maria M; Zagaynova, Elena V; Kuimova, Marina K

2017-01-01

Abnormal levels of viscosity in tissues and cells are known to be associated with disease and malfunction. While methods to measure bulk macroscopic viscosity of bio-tissues are well developed, imaging viscosity at the microscopic scale remains a challenge, especially in vivo. Molecular rotors are small synthetic viscosity-sensitive fluorophores in which fluorescence parameters are strongly correlated to the microviscosity of their immediate environment. Hence, molecular rotors represent a promising instrument for mapping of viscosity in living cells and tissues at the microscopic level. Quantitative measurements of viscosity can be achieved by recording time-resolved fluorescence decays of molecular rotor using fluorescence lifetime imaging microscopy (FLIM), which is also suitable for dynamic viscosity mapping, both in cellulo and in vivo. Among tools of experimental oncology, 3D tumour cultures, or spheroids, are considered a more adequate in vitro model compared to a cellular monolayer, and represent a less labour-intensive and more unified approach compared to animal tumour models. This chapter describes a methodology for microviscosity imaging in tumour spheroids using BODIPY-based molecular rotors and two photon-excited FLIM.

Cytogenetic and molecular genetic study on granular cell glioblastoma: a case report.

PubMed

Joo, Mee; Park, Sung-Hye; Chang, Sun Hee; Kim, Hanseong; Choi, Chan-Young; Lee, Chae-Heuck; Lee, Byung Hoon; Hwang, Yoon Joon

2013-02-01

Granular cell astrocytoma is a rare infiltrative malignant glioma with prominent granular cell change. Granular cell astrocytomas are biologically aggressive compared with conventional infiltrating astrocytomas of similar grades, but their genetic alterations are poorly known. We report a case of granular cell glioblastoma and its genetic and molecular features. Histologically, the tumor not only showed features typical of granular cell astrocytoma but also demonstrated frequent mitoses, pseudopalisading necrosis, and vascular endothelial hyperplasia, compatible with glioblastoma. Array-based comparative genomic hybridization and focused molecular genetic analyses demonstrated gain of chromosome 7; losses of chromosome 1p, 8p, 9p, 10, 13q, and 22q; amplification of epidermal growth factor receptor; and homozygous deletion of CDKN2A as well as MGMT promoter methylation. However, neither isocitrate dehydrogenase 1 mutation nor codeletion of 1p/19q was found. Our results indicate that granular cell glioblastomas, despite having its peculiar granular cell changes, share common molecular genetic features with conventional glioblastoma, especially the classical subtype. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of transcriptomic signature of post-Chernobyl and postradiotherapy thyroid tumors.

PubMed

Ory, Catherine; Ugolin, Nicolas; Hofman, Paul; Schlumberger, Martin; Likhtarev, Illya A; Chevillard, Sylvie

2013-11-01

We previously identified two highly discriminating and predictive radiation-induced transcriptomic signatures by comparing series of sporadic and postradiotherapy thyroid tumors (322-gene signature), and by reanalyzing a previously published data set of sporadic and post-Chernobyl thyroid tumors (106-gene signature). The aim of the present work was (i) to compare the two signatures in terms of gene expression deregulations and molecular features/pathways, and (ii) to test the capacity of the postradiotherapy signature in classifying the post-Chernobyl series of tumors and reciprocally of the post-Chernobyl signature in classifying the postradiotherapy-induced tumors. We now explored if postradiotherapy and post-Chernobyl papillary thyroid carcinomas (PTC) display common molecular features by comparing molecular pathways deregulated in the two tumor series, and tested the potential of gene subsets of the postradiotherapy signature to classify the post-Chernobyl series (14 sporadic and 12 post-Chernobyl PTC), and reciprocally of gene subsets of the post-Chernobyl signature to classify the postradiotherapy series (15 sporadic and 12 postradiotherapy PTC), by using conventional principal component analysis. We found that the five genes common to the two signatures classified the learning/training tumors (used to search these signatures) of both the postradiotherapy (seven PTC) and the post-Chernobyl (six PTC) thyroid tumor series as compared with the sporadic tumors (seven sporadic PTC in each series). Importantly, these five genes were also effective for classifying independent series of postradiotherapy (five PTC) and post-Chernobyl (six PTC) tumors compared to independent series of sporadic tumors (eight PTC and six PTC respectively; testing tumors). Moreover, part of each postradiotherapy (32 genes) and post-Chernobyl signature (16 genes) cross-classified the respective series of thyroid tumors. Finally, several molecular pathways deregulated in post-Chernobyl tumors matched those found to be deregulated in postradiotherapy tumors. Overall, our data suggest that thyroid tumors that developed following either external exposure or internal (131)I contamination shared common molecular features, related to DNA repair, oxidative and endoplasmic reticulum stresses, allowing their classification as radiation-induced tumors in comparison with sporadic counterparts, independently of doses and dose rates, which suggests there may be a "general" radiation-induced signature of thyroid tumors.

Comparative Transcriptome Analysis of Latex Reveals Molecular Mechanisms Underlying Increased Rubber Yield in Hevea brasiliensis Self-Rooting Juvenile Clones

PubMed Central

Li, Hui-Liang; Guo, Dong; Zhu, Jia-Hong; Wang, Ying; Chen, Xiong-Ting; Peng, Shi-Qing

2016-01-01

Rubber tree (Hevea brasiliensis) self-rooting juvenile clones (JCs) are promising planting materials for rubber production. In a comparative trial between self-rooting JCs and donor clones (DCs), self-rooting JCs exhibited better performance in rubber yield. To study the molecular mechanism associated with higher rubber yield in self-rooting JCs, we sequenced and comparatively analyzed the latex of rubber tree self-rooting JCs and DCs at the transcriptome level. Total raw reads of 34,632,012 and 35,913,020 bp were obtained from the library of self-rooting JCs and DCs, respectively, by using Illumina HiSeq 2000 sequencing technology. De novo assemblies yielded 54689 unigenes from the library of self-rooting JCs and DCs. Among 54689 genes, 1716 genes were identified as differentially expressed between self-rooting JCs and DCs via comparative transcript profiling. Functional analysis showed that the genes related to the mass of categories were differentially enriched between the two clones. Several genes involved in carbohydrate metabolism, hormone metabolism and reactive oxygen species scavenging were up-regulated in self-rooting JCs, suggesting that the self-rooting JCs provide sufficient molecular basis for the increased rubber yielding, especially in the aspects of improved latex metabolisms and latex flow. Some genes encoding epigenetic modification enzymes were also differentially expressed between self-rooting JCs and DCs. Epigenetic modifications may lead to gene differential expression between self-rooting JCs and DCs. These data will provide new cues to understand the molecular mechanism underlying the improved rubber yield of H. brasiliensis self-rooting clones. PMID:27555864

Comparative Transcriptome Analysis of Latex Reveals Molecular Mechanisms Underlying Increased Rubber Yield in Hevea brasiliensis Self-Rooting Juvenile Clones.

PubMed

Li, Hui-Liang; Guo, Dong; Zhu, Jia-Hong; Wang, Ying; Chen, Xiong-Ting; Peng, Shi-Qing

2016-01-01

Rubber tree (Hevea brasiliensis) self-rooting juvenile clones (JCs) are promising planting materials for rubber production. In a comparative trial between self-rooting JCs and donor clones (DCs), self-rooting JCs exhibited better performance in rubber yield. To study the molecular mechanism associated with higher rubber yield in self-rooting JCs, we sequenced and comparatively analyzed the latex of rubber tree self-rooting JCs and DCs at the transcriptome level. Total raw reads of 34,632,012 and 35,913,020 bp were obtained from the library of self-rooting JCs and DCs, respectively, by using Illumina HiSeq 2000 sequencing technology. De novo assemblies yielded 54689 unigenes from the library of self-rooting JCs and DCs. Among 54689 genes, 1716 genes were identified as differentially expressed between self-rooting JCs and DCs via comparative transcript profiling. Functional analysis showed that the genes related to the mass of categories were differentially enriched between the two clones. Several genes involved in carbohydrate metabolism, hormone metabolism and reactive oxygen species scavenging were up-regulated in self-rooting JCs, suggesting that the self-rooting JCs provide sufficient molecular basis for the increased rubber yielding, especially in the aspects of improved latex metabolisms and latex flow. Some genes encoding epigenetic modification enzymes were also differentially expressed between self-rooting JCs and DCs. Epigenetic modifications may lead to gene differential expression between self-rooting JCs and DCs. These data will provide new cues to understand the molecular mechanism underlying the improved rubber yield of H. brasiliensis self-rooting clones.

Comparing molecular composition of dissolved organic matter in soil and stream water: Influence of land use and chemical characteristics.

PubMed

Seifert, Anne-Gret; Roth, Vanessa-Nina; Dittmar, Thorsten; Gleixner, Gerd; Breuer, Lutz; Houska, Tobias; Marxsen, Jürgen

2016-11-15

Electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS) was used to examine the molecular composition of dissolved organic matter (DOM) from soils under different land use regimes and how the DOM composition in the catchment is reflected in adjacent streams. The study was carried out in a small area of the Schwingbach catchment, an anthropogenic-influenced landscape in central Germany. We investigated 30 different soil water samples from 4 sites and different depths (managed meadow (0-5cm, 40-50cm), deciduous forest (0-5cm), mixed-coniferous forest (0-5cm) and agricultural land (0-5cm, 40-50cm)) and 8 stream samples. 6194 molecular formulae and their magnitude-weighted parameters ((O/C)w, (H/C)w, (N/C)w, (AI-mod)w, (DBE/C)w, (DBE/O)w, (DBE-O)w, (C#)w, (MW)w) were used to describe the molecular composition of the samples. The samples can be roughly divided in three groups. Group 1 contains samples from managed meadow 40-50cm and stream water, which are characterized by high saturation compared to samples from group 2 including agricultural samples and samples from the surface meadow (0-5cm), which held more nitrogen containing and aromatic compounds. Samples from both forested sites (group 3) are characterized by higher molecular weight and O/C ratio. Environmental parameters vary between sites and among these parameters pH and nitrate significantly affect chemical composition of DOM. Results indicate that most DOM in streams is of terrestrial origin. However, 120 molecular formulae were detected only in streams and not in any of the soil samples. These compounds share molecular formulae with peptides, unsaturated aliphatics and saturated FA-CHO/FA-CHOX. Compounds only found in soil samples are much more aromatic, have more double bonds and a much lower H/C ratio but higher oxygen content, which indicates the availability of fresh plant material and less microbial processed material compared to stream samples. Copyright © 2016 Elsevier B.V. All rights reserved.

An investigation comparing traditional recitation instruction to computer tutorials which combine three-dimensional animation with varying levels of visual complexity, including digital video in teaching various chemistry topics

NASA Astrophysics Data System (ADS)

Graves, A. Palmer

This study examines the effect of increasing the visual complexity used in computer assisted instruction in general chemistry. Traditional recitation instruction was used as a control for the experiment. One tutorial presented a chemistry topic using 3-D animation showing molecular activity and symbolic representation of the macroscopic view of a chemical phenomenon. A second tutorial presented the same topic but simultaneously presented students with a digital video movie showing the phenomena and 3-D animation showing the molecular view of the phenomena. This experimental set-up was used in two different experiments during the first semester of college level general chemistry course. The topics covered were the molecular effect of heating water through the solid-liquid phase change and the kinetic molecular theory used in explaining pressure changes. The subjects used in the experiment were 236 college students enrolled in a freshman chemistry course at a large university. The data indicated that the simultaneous presentation of digital video, showing the solid to liquid phase change of water, with a molecular animation, showing the molecular behavior during the phase change, had a significant effect on student particulate understanding when compared to traditional recitation. Although the effect of the KMT tutorial was not statistically significant, there was a positive effect on student particulate understanding. The use of computer tutorial also had a significant effect on student attitude toward their comprehension of the lesson.

Evaluation of FTA paper and phenol for storage, extraction and molecular characterization of infectious bursal disease virus.

PubMed

Purvis, Linda B; Villegas, Pedro; Perozo, Francisco

2006-12-01

Infectious bursal disease virus (IBDV) is an important poultry pathogen and is distributed world wide that can cause immune suppression and lesions of the bursa of Fabricius. The main component of the virus, VP2, is not only responsible for the bird's immune response, but is important for the molecular identification of this virus as well. The nucleic acid of the virus must be adequately preserved to be analyzed by reverse-transcriptase PCR (RT-PCR) and sequenced for the molecular characterization of the field strain. Phenol inactivation has been the standard for IBDV tissue collection and international shipment; however, there have been some reports of interference with molecular detection capabilities when using phenol. Phenol is also a hazardous chemical and must be handled and shipped carefully. The ability to use the Flinders Technology Associates filter paper (FTA card) for inactivation of several avian pathogens has been proven previously, however no work has been published on its use in IBDV nucleic acid detection. Bursas from experimentally infected birds was imprinted on FTA cards, and then placed in phenol. Samples were evaluated and compared based on molecular detection capabilities between the two inactivation methods. The nucleic acid of the virus was detected in 85% of the FTA card inactivated samples compared to 71% in the phenol inactivated samples. Sequence analysis was performed on samples inactivated by both methods and no differences were found. When comparing the RNA stability at different temperatures, euthanized IBDV infected birds were held at two different temperatures before sampling. No differences were detected for FTA sampling; however, for tissues in phenol the nucleic acid was only detectable up to 2 h post-mortem in the tissues held at 4 degrees C prior to sampling. These findings indicate that the FTA card is an efficient and reliable alternative collection method for molecular detection and characterization of IBDV.

The development and application of a molecular community profiling strategy to identify polymicrobial bacterial DNA in the whole blood of septic patients.

PubMed

Faria, M M P; Conly, J M; Surette, M G

2015-10-16

The application of molecular based diagnostics in sepsis has had limited success to date. Molecular community profiling methods have indicated that polymicrobial infections are more common than suggested by standard clinical culture. A molecular profiling approach was developed to investigate the propensity for polymicrobial infections in patients predicted to have bacterial sepsis. Disruption of blood cells with saponin and hypotonic shock enabled the recovery of microbial cells with no significant changes in microbial growth when compared to CFU/ml values immediately prior to the addition of saponin. DNA extraction included a cell-wall digestion step with both lysozyme and mutanolysin, which increased the recovery of terminal restriction fragments by 2.4 fold from diverse organisms. Efficiencies of recovery and limits of detection using Illumina sequencing of the 16S rRNA V3 region were determined for both viable cells and DNA using mock bacterial communities inoculated into whole blood. Bacteria from pre-defined communities could be recovered following lysis and removal of host cells with >97% recovery of total DNA present. Applying the molecular profiling methodology to three septic patients in the intensive care unit revealed microbial DNA from blood had consistent alignment with cultured organisms from the primary infection site providing evidence for a bloodstream infection in the absence of a clinical lab positive blood culture result in two of the three cases. In addition, the molecular profiling indicated greater diversity was present in the primary infection sample when compared to clinical diagnostic culture. A method for analyzing bacterial DNA from whole blood was developed in order to characterize the bacterial DNA profile of sepsis infections. Preliminary results indicated that sepsis infections were polymicrobial in nature with the bacterial DNA recovered suggesting a more complex etiology when compared to blood culture data.

Molecular epidemiology of mastitis pathogens of dairy cattle and comparative relevance to humans.

PubMed

Zadoks, Ruth N; Middleton, John R; McDougall, Scott; Katholm, Jorgen; Schukken, Ynte H

2011-12-01

Mastitis, inflammation of the mammary gland, can be caused by a wide range of organisms, including gram-negative and gram-positive bacteria, mycoplasmas and algae. Many microbial species that are common causes of bovine mastitis, such as Escherichia coli, Klebsiella pneumoniae, Streptococcus agalactiae and Staphylococcus aureus also occur as commensals or pathogens of humans whereas other causative species, such as Streptococcus uberis, Streptococcus dysgalactiae subsp. dysgalactiae or Staphylococcus chromogenes, are almost exclusively found in animals. A wide range of molecular typing methods have been used in the past two decades to investigate the epidemiology of bovine mastitis at the subspecies level. These include comparative typing methods that are based on electrophoretic banding patterns, library typing methods that are based on the sequence of selected genes, virulence gene arrays and whole genome sequencing projects. The strain distribution of mastitis pathogens has been investigated within individual animals and across animals, herds, countries and host species, with consideration of the mammary gland, other animal or human body sites, and environmental sources. Molecular epidemiological studies have contributed considerably to our understanding of sources, transmission routes, and prognosis for many bovine mastitis pathogens and to our understanding of mechanisms of host-adaptation and disease causation. In this review, we summarize knowledge gleaned from two decades of molecular epidemiological studies of mastitis pathogens in dairy cattle and discuss aspects of comparative relevance to human medicine.

Molecular signals regulating translocation and toxicity of graphene oxide in the nematode Caenorhabditis elegans

NASA Astrophysics Data System (ADS)

Wu, Qiuli; Zhao, Yunli; Li, Yiping; Wang, Dayong

2014-09-01

Both in vitro and in vivo studies have demonstrated the toxic effects of graphene oxide (GO). However, the molecular basis for the translocation and toxicity of GO is still largely unclear. In the present study, we employed an in vivo Caenorhabditis elegans assay system to identify molecular signals involved in the control of the translocation and toxicity of GO. We identified 7 genes whose mutations altered both the translocation and toxicity of GO. Mutations of the hsp-16.48, gas-1, sod-2, sod-3, and aak-2 genes caused greater GO translocation into the body and toxic effects on both primary and secondary targeted organs compared with wild type; however, mutations of the isp-1 and clk-1 genes resulted in significantly decreased GO translocation into the body and toxicity on both primary and secondary targeted organs compared with wild-type. Moreover, mutations of the hsp-16.48, gas-1, sod-2, sod-3, and aak-2 genes caused increased intestinal permeability and prolonged mean defecation cycle length in GO-exposed nematodes, whereas mutations of the isp-1 and clk-1 genes resulted in decreased intestinal permeability in GO-exposed nematodes. Therefore, for the underlying mechanism, we hypothesize that both intestinal permeability and defecation behavior may have crucial roles in controlling the functions of the identified molecular signals. The molecular signals may further contribute to the control of transgenerational toxic effects of GO. Our results provide an important insight into understanding the molecular basis for the in vivo translocation and toxicity of GO.Both in vitro and in vivo studies have demonstrated the toxic effects of graphene oxide (GO). However, the molecular basis for the translocation and toxicity of GO is still largely unclear. In the present study, we employed an in vivo Caenorhabditis elegans assay system to identify molecular signals involved in the control of the translocation and toxicity of GO. We identified 7 genes whose mutations altered both the translocation and toxicity of GO. Mutations of the hsp-16.48, gas-1, sod-2, sod-3, and aak-2 genes caused greater GO translocation into the body and toxic effects on both primary and secondary targeted organs compared with wild type; however, mutations of the isp-1 and clk-1 genes resulted in significantly decreased GO translocation into the body and toxicity on both primary and secondary targeted organs compared with wild-type. Moreover, mutations of the hsp-16.48, gas-1, sod-2, sod-3, and aak-2 genes caused increased intestinal permeability and prolonged mean defecation cycle length in GO-exposed nematodes, whereas mutations of the isp-1 and clk-1 genes resulted in decreased intestinal permeability in GO-exposed nematodes. Therefore, for the underlying mechanism, we hypothesize that both intestinal permeability and defecation behavior may have crucial roles in controlling the functions of the identified molecular signals. The molecular signals may further contribute to the control of transgenerational toxic effects of GO. Our results provide an important insight into understanding the molecular basis for the in vivo translocation and toxicity of GO. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr02688h

Diverse assessment and active student engagement sustain deep learning: A comparative study of outcomes in two parallel introductory biochemistry courses.

PubMed

Bevan, Samantha J; Chan, Cecilia W L; Tanner, Julian A

2014-01-01

Although there is increasing evidence for a relationship between courses that emphasize student engagement and achievement of student deep learning, there is a paucity of quantitative comparative studies in a biochemistry and molecular biology context. Here, we present a pedagogical study in two contrasting parallel biochemistry introductory courses to compare student surface and deep learning. Surface and deep learning were measured quantitatively by a study process questionnaire at the start and end of the semester, and qualitatively by questionnaires and interviews with students. In the traditional lecture/examination based course, there was a dramatic shift to surface learning approaches through the semester. In the course that emphasized student engagement and adopted multiple forms of assessment, a preference for deep learning was sustained with only a small reduction through the semester. Such evidence for the benefits of implementing student engagement and more diverse non-examination based assessment has important implications for the design, delivery, and renewal of introductory courses in biochemistry and molecular biology. © 2014 The International Union of Biochemistry and Molecular Biology.

Molecular determinants of enzyme cold adaptation: comparative structural and computational studies of cold- and warm-adapted enzymes.

PubMed

Papaleo, Elena; Tiberti, Matteo; Invernizzi, Gaetano; Pasi, Marco; Ranzani, Valeria

2011-11-01

The identification of molecular mechanisms underlying enzyme cold adaptation is a hot-topic both for fundamental research and industrial applications. In the present contribution, we review the last decades of structural computational investigations on cold-adapted enzymes in comparison to their warm-adapted counterparts. Comparative sequence and structural studies allow the definition of a multitude of adaptation strategies. Different enzymes carried out diverse mechanisms to adapt to low temperatures, so that a general theory for enzyme cold adaptation cannot be formulated. However, some common features can be traced in dynamic and flexibility properties of these enzymes, as well as in their intra- and inter-molecular interaction networks. Interestingly, the current data suggest that a family-centered point of view is necessary in the comparative analyses of cold- and warm-adapted enzymes. In fact, enzymes belonging to the same family or superfamily, thus sharing at least the three-dimensional fold and common features of the functional sites, have evolved similar structural and dynamic patterns to overcome the detrimental effects of low temperatures.

Genetic, genomic, and molecular tools for studying the protoploid yeast, L. waltii.

PubMed

Di Rienzi, Sara C; Lindstrom, Kimberly C; Lancaster, Ragina; Rolczynski, Lisa; Raghuraman, M K; Brewer, Bonita J

2011-02-01

Sequencing of the yeast Kluyveromyces waltii (recently renamed Lachancea waltii) provided evidence of a whole genome duplication event in the lineage leading to the well-studied Saccharomyces cerevisiae. While comparative genomic analyses of these yeasts have proven to be extremely instructive in modeling the loss or maintenance of gene duplicates, experimental tests of the ramifications following such genome alterations remain difficult. To transform L. waltii from an organism of the computational comparative genomic literature into an organism of the functional comparative genomic literature, we have developed genetic, molecular and genomic tools for working with L. waltii. In particular, we have characterized basic properties of L. waltii (growth, ploidy, molecular karyotype, mating type and the sexual cycle), developed transformation, cell cycle arrest and synchronization protocols, and have created centromeric and non-centromeric vectors as well as a genome browser for L. waltii. We hope that these tools will be used by the community to follow up on the ideas generated by sequence data and lead to a greater understanding of eukaryotic biology and genome evolution. 2010 John Wiley & Sons, Ltd.

Genetic, genomic, and molecular tools for studying the protoploid yeast, L. waltii

PubMed Central

Di Rienzi, Sara C.; Lindstrom, Kimberly C.; Lancaster, Ragina; Rolczynski, Lisa; Raghuraman, M. K.; Brewer, Bonita J.

2011-01-01

Sequencing of the yeast Kluyveromyces waltii (recently renamed Lachancea waltii) provided evidence of a whole genome duplication event in the lineage leading to the well-studied Saccharomyces cerevisiae. While comparative genomic analyses of these yeasts have proven to be extremely instructive in modeling the loss or maintenance of gene duplicates, experimental tests of the ramifications following such genome alterations remain difficult. To transform L. waltii from an organism of the computational comparative genomic literature into an organism of the functional comparative genomic literature, we have developed genetic, molecular and genomic tools for working with L. waltii. In particular, we have characterized basic properties of L. waltii (growth, ploidy, molecular karyotype, mating type and the sexual cycle), developed transformation, cell cycle arrest and synchronization protocols, and have created centromeric and non-centromeric vectors as well as a genome browser for L. waltii. We hope that these tools will be used by the community to follow up on the ideas generated by sequence data and lead to a greater understanding of eukaryotic biology and genome evolution. PMID:21246627

A phylogenetic Kalman filter for ancestral trait reconstruction using molecular data.

PubMed

Lartillot, Nicolas

2014-02-15

Correlation between life history or ecological traits and genomic features such as nucleotide or amino acid composition can be used for reconstructing the evolutionary history of the traits of interest along phylogenies. Thus far, however, such ancestral reconstructions have been done using simple linear regression approaches that do not account for phylogenetic inertia. These reconstructions could instead be seen as a genuine comparative regression problem, such as formalized by classical generalized least-square comparative methods, in which the trait of interest and the molecular predictor are represented as correlated Brownian characters coevolving along the phylogeny. Here, a Bayesian sampler is introduced, representing an alternative and more efficient algorithmic solution to this comparative regression problem, compared with currently existing generalized least-square approaches. Technically, ancestral trait reconstruction based on a molecular predictor is shown to be formally equivalent to a phylogenetic Kalman filter problem, for which backward and forward recursions are developed and implemented in the context of a Markov chain Monte Carlo sampler. The comparative regression method results in more accurate reconstructions and a more faithful representation of uncertainty, compared with simple linear regression. Application to the reconstruction of the evolution of optimal growth temperature in Archaea, using GC composition in ribosomal RNA stems and amino acid composition of a sample of protein-coding genes, confirms previous findings, in particular, pointing to a hyperthermophilic ancestor for the kingdom. The program is freely available at www.phylobayes.org.

Surface induced molecular dynamics of thin lipid films confined to submicron cavities: A 1H multiple-quantum NMR study

NASA Astrophysics Data System (ADS)

Jagadeesh, B.; Prabhakar, A.; Demco, D. E.; Buda, A.; Blümich, B.

2005-03-01

The dynamics and molecular order of thin lipid (lecithin) films confined to 200, 100 and 20 nm cylindrical pores with varying surface coverage, were investigated by 1H multiple-quantum NMR. The results show that the molecular dynamics in the surface controlled layers are less hindered compared to those in the bulk. Dynamic heterogeneity among terminal CH 3 groups is evident. Enhanced dynamic freedom is observed for films with area per molecule, ˜ 128 Å 2. The results are discussed in terms of changes in the lipid molecular organization with respect to surface concentration, its plausible motional modes and dynamic heterogeneity.

A Cobalt Supramolecular Triple-Stranded Helicate-based Discrete Molecular Cage

PubMed Central

Mai, Hien Duy; Kang, Philjae; Kim, Jin Kyung; Yoo, Hyojong

2017-01-01

We report a strategy to achieve a discrete cage molecule featuring a high level of structural hierarchy through a multiple-assembly process. A cobalt (Co) supramolecular triple-stranded helicate (Co-TSH)-based discrete molecular cage (1) is successfully synthesized and fully characterized. The solid-state structure of 1 shows that it is composed of six triple-stranded helicates interconnected by four linking cobalt species. This is an unusual example of a highly symmetric cage architecture resulting from the coordination-driven assembly of metallosupramolecular modules. The molecular cage 1 shows much higher CO2 uptake properties and selectivity compared with the separate supramolecular modules (Co-TSH, complex 2) and other molecular platforms. PMID:28262690

Predicting RNA Duplex Dimerization Free-Energy Changes upon Mutations Using Molecular Dynamics Simulations.

PubMed

Sakuraba, Shun; Asai, Kiyoshi; Kameda, Tomoshi

2015-11-05

The dimerization free energies of RNA-RNA duplexes are fundamental values that represent the structural stability of RNA complexes. We report a comparative analysis of RNA-RNA duplex dimerization free-energy changes upon mutations, estimated from a molecular dynamics simulation and experiments. A linear regression for nine pairs of double-stranded RNA sequences, six base pairs each, yielded a mean absolute deviation of 0.55 kcal/mol and an R(2) value of 0.97, indicating quantitative agreement between simulations and experimental data. The observed accuracy indicates that the molecular dynamics simulation with the current molecular force field is capable of estimating the thermodynamic properties of RNA molecules.

Malaria Molecular Epidemiology: Lessons from the International Centers of Excellence for Malaria Research Network.

PubMed

Escalante, Ananias A; Ferreira, Marcelo U; Vinetz, Joseph M; Volkman, Sarah K; Cui, Liwang; Gamboa, Dionicia; Krogstad, Donald J; Barry, Alyssa E; Carlton, Jane M; van Eijk, Anna Maria; Pradhan, Khageswar; Mueller, Ivo; Greenhouse, Bryan; Pacheco, M Andreina; Vallejo, Andres F; Herrera, Socrates; Felger, Ingrid

2015-09-01

Molecular epidemiology leverages genetic information to study the risk factors that affect the frequency and distribution of malaria cases. This article describes molecular epidemiologic investigations currently being carried out by the International Centers of Excellence for Malaria Research (ICEMR) network in a variety of malaria-endemic settings. First, we discuss various novel approaches to understand malaria incidence and gametocytemia, focusing on Plasmodium falciparum and Plasmodium vivax. Second, we describe and compare different parasite genotyping methods commonly used in malaria epidemiology and population genetics. Finally, we discuss potential applications of molecular epidemiological tools and methods toward malaria control and elimination efforts. © The American Society of Tropical Medicine and Hygiene.

Nucleolar molecular signature of pluripotent stem cells.

PubMed

Pliss, Artem; Kuzmin, Andrey N; Kachynski, Aliaksandr V; Jiang, Houbo; Hu, Zhixing; Ren, Yong; Feng, Jian; Prasad, Paras N

2013-04-02

Induced pluripotent stem cells (iPSC) are generated by reprogramming somatic cells to the pluripotent state. Identification and quantitative characterization of changes in the molecular organization of the cell during the process of cellular reprogramming is valuable for stem cell research and advancement of its therapeutic applications. Here we employ quantitative Raman microspectroscopy and biomolecular component analysis (BCA) for a comparative analysis of the molecular composition of nucleoli in skin fibroblasts and iPSC derived from them. We report that the cultured fibroblasts obtained from different human subjects, share comparable concentrations of proteins, RNA, DNA, and lipids in the molecular composition of nucleoli. The nucleolar molecular environment is drastically changed in the corresponding iPSC. We measured that the transition from skin fibroblasts to iPSC is accompanied by a statistically significant increase in protein concentrations ~1.3-fold, RNA concentrations ~1.3-fold, and DNA concentrations ~1.4-fold, while no statistically significant difference was found for the lipid concentrations. The analysis of molecular vibrations associated with diverse aminoacids and protein conformations indicates that nucleoli of skin fibroblasts contain similar subsets of proteins, with prevalence of tyrosine. In iPSC, we observed a higher signal from tryptophan with an increase in the random coil and α helix protein conformations, indicating changes in the subset of nucleolar proteins during cell reprogramming. At the same time, the concentrations of major types of macromolecules and protein conformations in the nucleoli of iPSC and human embryonic stem cells (hESC) were found to be similar. We discuss these results in the context of nucleolar function and conclude that the nucleolar molecular content is correlated with the cellular differentiation status. The approach described here shows the potential for spectroscopically monitoring changes in macromolecular organization of the cell at different stages of reprogramming.

Molecular weight analyses and enzymatic degradation profiles of the soft-tissue fillers Belotero Balance, Restylane, and Juvéderm Ultra.

PubMed

Flynn, Timothy Corcoran; Thompson, David H; Hyun, Seok-Hee

2013-10-01

In this study, the authors sought to determine the molecular weight distribution of three hyaluronic acids-Belotero Balance, Restylane, and Juvéderm Ultra-and their rates of degradation following exposure to hyaluronidase. Lot consistency of Belotero Balance also was analyzed. Three lots of Belotero Balance were analyzed using liquid chromatography techniques. The product was found to have high-molecular-weight and low-molecular-weight species. One lot of Belotero Balance was compared to one lot each of Juvéderm Ultra and Restylane. Molecular weights of the species were analyzed. The hyaluronic acids were exposed to ovine testicular hyaluronidase at six time points-baseline and 0.5, 1, 2, 6, and 24 hours-to determine degradation rates. Belotero Balance lots were remarkably consistent. Belotero Balance had the largest high-molecular-weight species, followed by Juvéderm Ultra and Restylane (p < 0.001). Low-molecular-weight differences among all three hyaluronic acids were not statistically significant. Percentages of high-molecular-weight polymer differ among the three materials, with Belotero Balance having the highest fraction of high-molecular-weight polymer. Degradation of the high-molecular-weight species over time showed different molecular weights of the high-molecular-weight fraction. Rates of degradation of the hyaluronic acids following exposure to ovine testicular hyaluronidase were similar. All hyaluronic acids were fully degraded at 24 hours. Fractions of high-molecular-weight polymer differ across the hyaluronic acids tested. The low-molecular-weight differences are not statistically significant. The high-molecular-weight products have different molecular weights at the 0.5- and 2-hour time points when exposed to ovine testicular hyaluronidase and are not statistically different at 24 hours.

Structural analysis of Ca²⁺ dependent and Ca²⁺ independent type II antifreeze proteins: a comparative molecular dynamics simulation study.

PubMed

Kundu, Sangeeta; Roy, Debjani

2012-09-01

Comparative molecular dynamics simulations of Ca²⁺ dependent psychrophilic type II antifreeze protein (AFP) from herring (Clupea harengus) (hAFP) and Ca²⁺ dependent type II antifreeze protein from long snout poacher (Brachyopsis rostratus) (lpAFP) have been performed for 10 ns each at five different temperatures. We have tried to investigate whether the Ca²⁺ dependent protein obtains any advantage in nature over the independent one. To this end the dynamic properties of these two proteins have been compared in terms of secondary structure content, molecular flexibility, solvent accessibility, intra molecular hydrogen bonds and protein-solvent interactions. At 298 and 373 K the flexibility of the Ca²⁺ independent molecule is higher which indicates that Ca²⁺ could contribute to stabilize the structure. The thermal unfolding pathways of the two proteins have also been monitored. The rate of unfolding is similar up to 373 K, beyond that hAFP shows faster unfolding than lpAFP. The essential subspaces explored by the simulations of hAFP and lpAFP at different temperatures are significantly different as revealed from principal component analysis. Our results may help in understanding the role of Ca²⁺ for hAFP to express antifreeze activity. Furthermore our study may also help in elucidating the molecular basis of thermostability of two structurally similar proteins, which perform the same function in different manner, one in presence of Ca²⁺, and the other in absence of the same. Copyright © 2012 Elsevier Inc. All rights reserved.

Combining comparative proteomics and molecular genetics uncovers regulators of synaptic and axonal stability and degeneration in vivo.

PubMed

Wishart, Thomas M; Rooney, Timothy M; Lamont, Douglas J; Wright, Ann K; Morton, A Jennifer; Jackson, Mandy; Freeman, Marc R; Gillingwater, Thomas H

2012-01-01

Degeneration of synaptic and axonal compartments of neurons is an early event contributing to the pathogenesis of many neurodegenerative diseases, but the underlying molecular mechanisms remain unclear. Here, we demonstrate the effectiveness of a novel "top-down" approach for identifying proteins and functional pathways regulating neurodegeneration in distal compartments of neurons. A series of comparative quantitative proteomic screens on synapse-enriched fractions isolated from the mouse brain following injury identified dynamic perturbations occurring within the proteome during both initiation and onset phases of degeneration. In silico analyses highlighted significant clustering of proteins contributing to functional pathways regulating synaptic transmission and neurite development. Molecular markers of degeneration were conserved in injury and disease, with comparable responses observed in synapse-enriched fractions isolated from mouse models of Huntington's disease (HD) and spinocerebellar ataxia type 5. An initial screen targeting thirteen degeneration-associated proteins using mutant Drosophila lines revealed six potential regulators of synaptic and axonal degeneration in vivo. Mutations in CALB2, ROCK2, DNAJC5/CSP, and HIBCH partially delayed injury-induced neurodegeneration. Conversely, mutations in DNAJC6 and ALDHA1 led to spontaneous degeneration of distal axons and synapses. A more detailed genetic analysis of DNAJC5/CSP mutants confirmed that loss of DNAJC5/CSP was neuroprotective, robustly delaying degeneration in axonal and synaptic compartments. Our study has identified conserved molecular responses occurring within synapse-enriched fractions of the mouse brain during the early stages of neurodegeneration, focused on functional networks modulating synaptic transmission and incorporating molecular chaperones, cytoskeletal modifiers, and calcium-binding proteins. We propose that the proteins and functional pathways identified in the current study represent attractive targets for developing therapeutics aimed at modulating synaptic and axonal stability and neurodegeneration in vivo.

Manipulating the Lewis antigen specificity of the cholesterol-dependent cytolysin lectinolysin

PubMed Central

Lawrence, Sara L.; Feil, Susanne C.; Holien, Jessica K.; Kuiper, Michael J.; Doughty, Larissa; Dolezal, Olan; Mulhern, Terrence D.; Tweten, Rodney K.; Parker, Michael W.

2012-01-01

The cholesterol-dependent cytolysins (CDCs) attack cells by punching large holes in their membranes. Lectinolysin from Streptococcus mitis is unique among CDCs due to the presence of an N-terminal lectin domain that enhances the pore-forming activity of the toxin. We recently determined the crystal structures of the lectin domain in complex with various glycans. These structures revealed the molecular basis for the Lewis antigen specificity of the toxin. Based on this information we have used in silico molecular modeling to design a mutant toxin, which we predicted would increase its specificity for Lewis y, an antigen found on the surface of cancer cells. Surprisingly, we found by surface plasmon resonance binding experiments that the resultant mutant lectin domain exhibited higher specificity for Lewis b antigens instead. We then undertook comparative crystallographic and molecular dynamics simulation studies of the wild-type and mutant lectin domains to understand the molecular basis for the disparity between the theoretical and experimental results. The crystallographic results revealed that the net number of interactions between Lewis y and wild-type versus mutant was unchanged whereas there was a loss of a hydrogen bond between mutant and Lewis b compared to wild-type. In contrast, the molecular dynamics studies revealed that the Lewis b antigen spent more time in the binding pocket of the mutant compared to wild-type and the reverse was true for Lewis y. The results of these simulation studies are consistent with the conclusions drawn from the surface plasmon resonance studies. This work is part of a program to engineer lectinolysin so that it will target and kill specific cells in human diseases. PMID:23181061

Fluorescence-correlation spectroscopy study of molecular transport within reversed-phase chromatographic particles compared to planar model surfaces.

PubMed

Cooper, Justin; Harris, Joel M

2014-12-02

Reversed-phase liquid chromatography (RPLC) is a widely used technique for molecular separations. Stationary-phase materials for RPLC generally consist of porous silica-gel particles functionalized with n-alkane ligands. Understanding motions of molecules within the interior of these particles is important for developing efficient chromatographic materials and separations. To characterize these dynamics, time-resolved spectroscopic methods (photobleach recovery, fluorescence correlation, single-molecule imaging) have been adapted to measure molecular diffusion rates, typically at n-alkane-modified planar silica surfaces, which serve as models of chromatographic interfaces. A question arising from these studies is how dynamics of molecules on a planar surface relate to motions of molecules within the interior of a porous chromatographic particle. In this paper, imaging-fluorescence-correlation spectroscopy is used to measure diffusion rates of a fluorescent probe molecule 1,1'-dioctadecyl-3,3,3'3'-tetramethylindocarbocyanine perchlorate (DiI) within authentic RPLC porous silica particles and compared with its diffusion at a planar C18-modified surface. The results show that surface diffusion on the planar C18 substrate is much faster than the diffusion rate of the probe molecule through a chromatographic particle. Surface diffusion within porous particles, however, is governed by molecular trajectories along the tortuous contours of the interior surface of the particles. By accounting for the greater surface area that a molecule must explore to diffuse macroscopic distances through the particle, the molecular-scale diffusion rates on the two surfaces can be compared, and they are virtually identical. These results provide support for the relevance of surface-diffusion measurements made on planar model surfaces to the dynamic behavior of molecules on the internal surfaces of porous chromatographic particles.

Antifungal drug susceptibility and phylogenetic diversity among Cryptococcus isolates from dogs and cats in North America.

PubMed

Singer, Lisa M; Meyer, Wieland; Firacative, Carolina; Thompson, George R; Samitz, Eileen; Sykes, Jane E

2014-06-01

Molecular types of the Cryptococcus neoformans/Cryptococcus gattii species complex that infect dogs and cats differ regionally and with host species. Antifungal drug susceptibility can vary with molecular type, but the susceptibility of Cryptococcus isolates from dogs and cats is largely unknown. Cryptococcus isolates from 15 dogs and 27 cats were typed using URA5 restriction fragment length polymorphism analysis (RFLP), PCR fingerprinting, and multilocus sequence typing (MLST). Susceptibility was determined using a microdilution assay (Sensititre YeastOne; Trek Diagnostic Systems). MICs were compared among groups. The 42 isolates studied comprised molecular types VGI (7%), VGIIa (7%), VGIIb (5%), VGIIc (5%), VGIII (38%), VGIV (2%), VNI (33%), and VNII (2%), as determined by URA5 RFLP. The VGIV isolate was more closely related to VGIII according to MLST. All VGIII isolates were from cats. All sequence types identified from veterinary isolates clustered with isolates from humans. VGIII isolates showed considerable genetic diversity compared with other Cryptococcus molecular types and could be divided into two major subgroups. Compared with C. neoformans MICs, C. gattii MICs were lower for flucytosine, and VGIII MICs were lower for flucytosine and itraconazole. For all drugs except itraconazole, C. gattii isolates exhibited a wider range of MICs than C. neoformans. MICs varied with Cryptococcus species and molecular type in dogs and cats, and MICs of VGIII isolates were most variable and may reflect phylogenetic diversity in this group. Because sequence types of dogs and cats reflect those infecting humans, these observations may also have implications for treatment of human cryptococcosis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Bioinformatics analysis on molecular mechanism of rheum officinale in treatment of jaundice

NASA Astrophysics Data System (ADS)

Shan, Si; Tu, Jun; Nie, Peng; Yan, Xiaojun

2017-01-01

Objective: To study the molecular mechanism of Rheum officinale in the treatment of Jaundice by building molecular networks and comparing canonical pathways. Methods: Target proteins of Rheum officinale and related genes of Jaundice were searched from Pubchem and Gene databases online respectively. Molecular networks and canonical pathways comparison analyses were performed by Ingenuity Pathway Analysis (IPA). Results: The molecular networks of Rheum officinale and Jaundice were complex and multifunctional. The 40 target proteins of Rheum officinale and 33 Homo sapiens genes of Jaundice were found in databases. There were 19 common pathways both related networks. Rheum officinale could regulate endothelial differentiation, Interleukin-1B (IL-1B) and Tumor Necrosis Factor (TNF) in these pathways. Conclusions: Rheum officinale treat Jaundice by regulating many effective nodes of Apoptotic pathway and cellular immunity related pathways.

[Molecular typing methods for Pasteurella multocida-A review].

PubMed

Peng, Zhong; Liang, Wan; Wu, Bin

2016-10-04

Pasteurella multocida is an important gram-negative pathogenic bacterium that could infect wide ranges of animals. Humans could also be infected by P. multocida via animal bite or scratching. Current typing methods for P. multocida include serological typing methods and molecular typing methods. Of them, serological typing methods are based on immunological assays, which are too complicated for clinical bacteriological studies. However, the molecular methods including multiple PCRs and multilocus sequence typing (MLST) methods are more suitable for bacteriological studies of P. multocida in clinic, with their simple operation, high efficiency and accurate detection compared to the traditional serological typing methods, they are therefore widely used. In the current review, we briefly describe the molecular typing methods for P. multocida. Our aim is to provide a knowledge-foundation for clinical bacteriological investigation especially the molecular investigation for P. multocida.

High molecular diversity of extraterrestrial organic matter in Murchison meteorite revealed 40 years after its fall

PubMed Central

Schmitt-Kopplin, Philippe; Gabelica, Zelimir; Gougeon, Régis D.; Fekete, Agnes; Kanawati, Basem; Harir, Mourad; Gebefuegi, Istvan; Eckel, Gerhard; Hertkorn, Norbert

2010-01-01

Numerous descriptions of organic molecules present in the Murchison meteorite have improved our understanding of the early interstellar chemistry that operated at or just before the birth of our solar system. However, all molecular analyses were so far targeted toward selected classes of compounds with a particular emphasis on biologically active components in the context of prebiotic chemistry. Here we demonstrate that a nontargeted ultrahigh-resolution molecular analysis of the solvent-accessible organic fraction of Murchison extracted under mild conditions allows one to extend its indigenous chemical diversity to tens of thousands of different molecular compositions and likely millions of diverse structures. This molecular complexity, which provides hints on heteroatoms chronological assembly, suggests that the extraterrestrial chemodiversity is high compared to terrestrial relevant biological- and biogeochemical-driven chemical space. PMID:20160129

Parallel, stochastic measurement of molecular surface area.

PubMed

Juba, Derek; Varshney, Amitabh

2008-08-01

Biochemists often wish to compute surface areas of proteins. A variety of algorithms have been developed for this task, but they are designed for traditional single-processor architectures. The current trend in computer hardware is towards increasingly parallel architectures for which these algorithms are not well suited. We describe a parallel, stochastic algorithm for molecular surface area computation that maps well to the emerging multi-core architectures. Our algorithm is also progressive, providing a rough estimate of surface area immediately and refining this estimate as time goes on. Furthermore, the algorithm generates points on the molecular surface which can be used for point-based rendering. We demonstrate a GPU implementation of our algorithm and show that it compares favorably with several existing molecular surface computation programs, giving fast estimates of the molecular surface area with good accuracy.

Molecular dynamics computer simulation of permeation in solids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pohl, P.I.; Heffelfinger, G.S.; Fisler, D.K.

1997-12-31

In this work the authors simulate permeation of gases and cations in solid models using molecular mechanics and a dual control volume grand canonical molecular dynamics technique. The molecular sieving nature of microporous zeolites are discussed and compared with that for amorphous silica made by sol-gel methods. One mesoporous and one microporous membrane model are tested with Lennard-Jones gases corresponding to He, H{sub 2}, Ar and CH{sub 4}. The mesoporous membrane model clearly follows a Knudsen diffusion mechanism, while the microporous model having a hard-sphere cutoff pore diameter of {approximately}3.4 {angstrom} demonstrates molecular sieving of the methane ({sigma} = 3.8more » {angstrom}) but anomalous behavior for Ar ({sigma} = 3.4 {angstrom}). Preliminary results of Ca{sup +} diffusion in calcite and He/H{sub 2} diffusion in polyisobutylene are also presented.« less

High molecular diversity of extraterrestrial organic matter in Murchison meteorite revealed 40 years after its fall.

PubMed

Schmitt-Kopplin, Philippe; Gabelica, Zelimir; Gougeon, Régis D; Fekete, Agnes; Kanawati, Basem; Harir, Mourad; Gebefuegi, Istvan; Eckel, Gerhard; Hertkorn, Norbert

2010-02-16

Numerous descriptions of organic molecules present in the Murchison meteorite have improved our understanding of the early interstellar chemistry that operated at or just before the birth of our solar system. However, all molecular analyses were so far targeted toward selected classes of compounds with a particular emphasis on biologically active components in the context of prebiotic chemistry. Here we demonstrate that a nontargeted ultrahigh-resolution molecular analysis of the solvent-accessible organic fraction of Murchison extracted under mild conditions allows one to extend its indigenous chemical diversity to tens of thousands of different molecular compositions and likely millions of diverse structures. This molecular complexity, which provides hints on heteroatoms chronological assembly, suggests that the extraterrestrial chemodiversity is high compared to terrestrial relevant biological- and biogeochemical-driven chemical space.

Tribological characteristics of a composite total-surface hip replacement

NASA Technical Reports Server (NTRS)

Jones, W. R., Jr.; Roberts, J. C.; Ling, F. F.

1982-01-01

Continuous fiber, woven E glass composite femoral shells having the same elastic properties as bone were fabricated. The shells were then encrusted with filled epoxy wear resistant coatings and run dry against ultrahigh molecular weight polyethylene acetabular cups in 42,000 and 250,000 cycle wear tests on a total hip simulator. The tribological characteristics of these continuous fiber particulate composite femoral shells articulating with ultrahigh molecular weight polyethylene acetabular cups were comparable to those of a vitallium ball articulating with an ultrahigh molecular weight polyethylene acetabular cup.

The evolution of dorsal-ventral patterning mechanisms in insects.

PubMed

Lynch, Jeremy A; Roth, Siegfried

2011-01-15

The gene regulatory network (GRN) underpinning dorsal-ventral (DV) patterning of the Drosophila embryo is among the most thoroughly understood GRNs, making it an ideal system for comparative studies seeking to understand the evolution of development. With the emergence of widely applicable techniques for testing gene function, species with sequenced genomes, and multiple tractable species with diverse developmental modes, a phylogenetically broad and molecularly deep understanding of the evolution of DV axis formation in insects is feasible. Here, we review recent progress made in this field, compare our emerging molecular understanding to classical embryological experiments, and suggest future directions of inquiry.

Detection of high molecular weight proteins by MALDI imaging mass spectrometry.

PubMed

Mainini, Veronica; Bovo, Giorgio; Chinello, Clizia; Gianazza, Erica; Grasso, Marco; Cattoretti, Giorgio; Magni, Fulvio

2013-06-01

MALDI imaging mass spectrometry (IMS) is a unique technology to explore the spatial distribution of biomolecules directly on tissues. It allows the in situ investigation of a large number of small proteins and peptides. Detection of high molecular weight proteins through MALDI IMS still represents an important challenge, as it would allow the direct investigation of the distribution of more proteins involved in biological processes, such as cytokines, enzymes, neuropeptide precursors and receptors. In this work we compare the traditional method performed with sinapinic acid with a comparable protocol using ferulic acid as the matrix. Data show a remarkable increase of signal acquisition in the mass range of 20k to 150k Th. Moreover, we report molecular images of biomolecules above 70k Th, demonstrating the possibility of expanding the application of this technology both in clinical investigations and basic science.

Low Molecular Weight Polymethacrylates as Multi-Functional Lubricant Additives

DOE PAGES

Cosimbescu, Lelia; Vellore, Azhar; Shantini Ramasamy, Uma; ...

2018-04-24

In this study, low molecular weight, moderately polar polymethacrylate polymers are explored as potential multi-functional lubricant additives. The performance of these novel additives in base oil is evaluated in terms of their viscosity index, shear stability, and friction-and-wear. The new compounds are compared to two benchmarks, a typical polymeric viscosity modifier and a fully-formulated oil. Results show that the best performing of the new polymers exhibit viscosity index and friction comparable to that of both benchmarks, far superior shear stability to either benchmark (as much as 15x lower shear loss), and wear reduction significantly better than a typical viscosity modifiermore » (lower wear volume by a factor of 2-3). The findings also suggest that the polarity and molecular weight of the polymers affect their performance which suggests future synthetic strategies may enable this new class of additives to replace multiple additives in typical lubricant formulations.« less

Hepatocellular carcinoma treatment: a comparative review of emerging growth factor receptor antagonists.

PubMed

Lee, Su Jin; Lim, Ho Yeong

2017-06-01

Hepatocellular carcinoma (HCC) is a leading cause of death worldwide. Over the last decade, sorafenib has been the only available therapeutic option for advanced HCC, although regorafenib recently showed a survival benefit compared with placebo in a second-line setting. Areas covered: This review discusses key published and ongoing studies with targeted agents in HCC, molecular targets of HCC, the mechanism of resistance to sorafenib, and the role of biomarker-enriched clinical trials. Expert opinion: The multiplicity of drivers and the existence of substantial molecular heterogeneity limit the benefits of targeted therapies in HCC. Based on molecular biology developments, a few biomarker-enriched clinical trials that target candidate driver genes are ongoing, and the outcomes of these are highly anticipated. Poor availability of tumor tissue and tumor heterogeneity in patients with HCC make liquid biopsy a very attractive option, although this technique remains to be validated.

Low Molecular Weight Polymethacrylates as Multi-Functional Lubricant Additives

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cosimbescu, Lelia; Vellore, Azhar; Shantini Ramasamy, Uma

In this study, low molecular weight, moderately polar polymethacrylate polymers are explored as potential multi-functional lubricant additives. The performance of these novel additives in base oil is evaluated in terms of their viscosity index, shear stability, and friction-and-wear. The new compounds are compared to two benchmarks, a typical polymeric viscosity modifier and a fully-formulated oil. Results show that the best performing of the new polymers exhibit viscosity index and friction comparable to that of both benchmarks, far superior shear stability to either benchmark (as much as 15x lower shear loss), and wear reduction significantly better than a typical viscosity modifiermore » (lower wear volume by a factor of 2-3). The findings also suggest that the polarity and molecular weight of the polymers affect their performance which suggests future synthetic strategies may enable this new class of additives to replace multiple additives in typical lubricant formulations.« less

Spotting the difference in molecular dynamics simulations of biomolecules

NASA Astrophysics Data System (ADS)

Sakuraba, Shun; Kono, Hidetoshi

2016-08-01

Comparing two trajectories from molecular simulations conducted under different conditions is not a trivial task. In this study, we apply a method called Linear Discriminant Analysis with ITERative procedure (LDA-ITER) to compare two molecular simulation results by finding the appropriate projection vectors. Because LDA-ITER attempts to determine a projection such that the projections of the two trajectories do not overlap, the comparison does not suffer from a strong anisotropy, which is an issue in protein dynamics. LDA-ITER is applied to two test cases: the T4 lysozyme protein simulation with or without a point mutation and the allosteric protein PDZ2 domain of hPTP1E with or without a ligand. The projection determined by the method agrees with the experimental data and previous simulations. The proposed procedure, which complements existing methods, is a versatile analytical method that is specialized to find the "difference" between two trajectories.

Thermophysical properties of liquid UO2, ZrO2 and corium by molecular dynamics and predictive models

NASA Astrophysics Data System (ADS)

Kim, Woong Kee; Shim, Ji Hoon; Kaviany, Massoud

2017-08-01

Predicting the fate of accident-melted nuclear fuel-cladding requires the understanding of the thermophysical properties which are lacking or have large scatter due to high-temperature experimental challenges. Using equilibrium classical molecular dynamics (MD), we predict the properties of melted UO2 and ZrO2 and compare them with the available experimental data and the predictive models. The existing interatomic potential models have been developed mainly for the polymorphic solid phases of these oxides, so they cannot be used to predict all the properties accurately. We compare and decipher the distinctions of those MD predictions using the specific property-related autocorrelation decays. The predicted properties are density, specific heat, heat of fusion, compressibility, viscosity, surface tension, and the molecular and electronic thermal conductivities. After the comparisons, we provide readily usable temperature-dependent correlations (including UO2-ZrO2 compounds, i.e. corium melt).

Comparative virulence and molecular diversity of stripe rust (Puccinia striiformis f. sp. tritici) collections from Pakistan and United States

USDA-ARS?s Scientific Manuscript database

Information on virulence and molecular diversity of Puccinia striiformis f. sp. tritici (Pst) is a pre-requisite for mitigating the substantial yield losses caused by the stripe rust pathogen in Pakistan, the United States and other countries of the world. This study was undertaken to analyze both v...

Comparing Classical Water Models Using Molecular Dynamics to Find Bulk Properties

ERIC Educational Resources Information Center

Kinnaman, Laura J.; Roller, Rachel M.; Miller, Carrie S.

2018-01-01

A computational chemistry exercise for the undergraduate physical chemistry laboratory is described. In this exercise, students use the molecular dynamics package Amber to generate trajectories of bulk liquid water for 4 different water models (TIP3P, OPC, SPC/E, and TIP4Pew). Students then process the trajectory to calculate structural (radial…

MOLECULAR STRUCTURAL FACTORS IN COMPETITIVE INHIBITION OF SUGAR TRANSPORT

DOE Office of Scientific and Technical Information (OSTI.GOV)

LeFevre, P.G.

1959-07-10

The high potency of phloretin as a competitive inhibitor of the human red cell's monosaccharide transport system is not shared by any of several molecular fragments of phloretin, but is duplicated in certain artificial estrogens resembling phloretin in respect to the spacing between terminal phenolic---OH groups. Related molecules which are slightly less extendible are comparatively inactive. (auth)

The Effect That Comparing Molecular Animations of Varying Accuracy Has on Students' Submicroscopic Explanations

ERIC Educational Resources Information Center

Kelly, Resa M.; Akaygun, Sevil; Hansen, Sarah J. R.; Villalta-Cerdas, Adrian

2017-01-01

In this qualitative study, we examined how a group of seventeen first semester General Chemistry students responded when they were shown contrasting molecular animations of a reduction-oxidation (redox) reaction between solid copper and aqueous silver nitrate for which they first viewed a video of the actual experiment. The animations contrasted…

Using Computer Animation and Illustration Activities to Improve High School Students' Achievement in Molecular Genetics

ERIC Educational Resources Information Center

Marbach-Ad, Gili; Rotbain, Yosi; Stavy, Ruth

2008-01-01

Our main goal in this study was to determine whether the use of computer animation and illustration activities in high school can contribute to student achievement in molecular genetics. Three comparable groups of eleventh- and twelfth-grade students participated: the control group (116 students) was taught in the traditional lecture format,…

Comparative Genomics Reveals Accelerated Evolution in Conserved Pathways during the Diversification of Anole Lizards

PubMed Central

Tollis, Marc; Hutchins, Elizabeth D; Stapley, Jessica; Rupp, Shawn M; Eckalbar, Walter L; Maayan, Inbar; Lasku, Eris; Infante, Carlos R; Dennis, Stuart R; Robertson, Joel A; May, Catherine M; Bermingham, Eldredge; DeNardo, Dale F; Hsieh, Shi-Tong Tonia; Kulathinal, Rob J; McMillan, William Owen; Menke, Douglas B; Pratt, Stephen C; Rawls, Jeffery Alan; Sanjur, Oris; Wilson-Rawls, Jeanne; Wilson Sayres, Melissa A; Fisher, Rebecca E

2018-01-01

Abstract Squamates include all lizards and snakes, and display some of the most diverse and extreme morphological adaptations among vertebrates. However, compared with birds and mammals, relatively few resources exist for comparative genomic analyses of squamates, hampering efforts to understand the molecular bases of phenotypic diversification in such a speciose clade. In particular, the ∼400 species of anole lizard represent an extensive squamate radiation. Here, we sequence and assemble the draft genomes of three anole species—Anolis frenatus, Anolis auratus, and Anolis apletophallus—for comparison with the available reference genome of Anolis carolinensis. Comparative analyses reveal a rapid background rate of molecular evolution consistent with a model of punctuated equilibrium, and strong purifying selection on functional genomic elements in anoles. We find evidence for accelerated evolution in genes involved in behavior, sensory perception, and reproduction, as well as in genes regulating limb bud development and hindlimb specification. Morphometric analyses of anole fore and hindlimbs corroborated these findings. We detect signatures of positive selection across several genes related to the development and regulation of the forebrain, hormones, and the iguanian lizard dewlap, suggesting molecular changes underlying behavioral adaptations known to reinforce species boundaries were a key component in the diversification of anole lizards. PMID:29360978

Comparative Evaluation of U.S. Brand and Generic Intravenous Sodium Ferric Gluconate Complex in Sucrose Injection: Physicochemical Characterization

PubMed Central

Sun, Dajun; Rouse, Rodney; Patel, Vikram; Wu, Yong; Zheng, Jiwen; Karmakar, Alokita; Patri, Anil K.; Keire, David; Ma, Jia; Jiang, Wenlei

2018-01-01

The objective of this study was to evaluate physicochemical equivalence between brand (i.e., Ferrlecit) and generic sodium ferric gluconate (SFG) in sucrose injection by conducting a series of comparative in vitro characterizations using advanced analytical techniques. The elemental iron and carbon content, thermal properties, viscosity, particle size, zeta potential, sedimentation coefficient, and molecular weight were determined. There was no noticeable difference between brand and generic SFG in sucrose injection for the above physical parameters evaluated, except for the sedimentation coefficient determined by sedimentation velocity analytical ultracentrifugation (SV-AUC) and molecular weight by asymmetric field flow fractionation-multi-angle light scattering (AFFF-MALS). In addition, brand and generic SFG complex products showed comparable molecular weight distributions when determined by gel permeation chromatography (GPC). The observed minor differences between brand and generic SFG, such as sedimentation coefficient, do not impact their biological activities in separate studies of in vitro cellular uptake and rat biodistribution. Coupled with the ongoing clinical study comparing the labile iron level in healthy volunteers, the FDA-funded post-market studies intended to illustrate comprehensive surveillance efforts ensuring safety and efficacy profiles of generic SFG complex in sucrose injection, and also to shed new light on the approval standards on generic parenteral iron colloidal products. PMID:29303999

Comparative transcriptome analysis of Sogatella furcifera (Horváth) exposed to different insecticides.

PubMed

Zhou, Cao; Yang, Hong; Wang, Zhao; Long, Gui-Yun; Jin, Dao-Chao

2018-06-08

White-backed planthopper, Sogatella furcifera (Horváth) (Hemiptera: Delphacidae), one of the main agricultural insect pests in China, is resistant to a wide variety of insecticides. We used transcriptome analysis to compare the expression patterns of resistance- and stress-response genes in S. furcifera subjected to imidacloprid, deltamethrin, and triazophos stress, to determine the molecular mechanisms of resistance to these insecticides. A comparative analysis of gene expression under imidacloprid, deltamethrin, and triazophos stress revealed 1,123, 841, and 316 upregulated unigenes, respectively, compared to the control. These upregulated genes included seven P450s (two CYP2 clade, three CYP3 clade, and two CYP4 clade), one GST, one ABC transporter (ABCF), and seven Hsps (one 90 and six Hsp70s) under imidacloprid stress; one P450 (CYP3 clade), two ABC transporters (one ABCF and one ABCD), and one Hsp (Hsp90) under deltamethrin stress; one P450 (CYP3 clade) and one ABC transporter (ABCF) under triazophos stress. In addition, 80 genes were commonly upregulated in response to the three insecticide treatments, including laminin, larval cuticle protein, and fasciclin, which are associated with epidermal formation. These results provide a valuable resource for the molecular characterisation of insecticide action in S. furcifera, especially the molecular characteristics of insecticide cross resistance.

Electron Transport through Porphyrin Molecular Junctions

NASA Astrophysics Data System (ADS)

Zhou, Qi

The goal of this work is to study the properties that would affect the electron transport through a porphyrin molecular junction. This work contributes to the field of electron transport in molecular junctions in the following 3 aspects. First of all, by carrying out experiments comparing the conductance of the iron (III) porphyrin (protected) and the free base porphyrin (protected), it is confirmed that the molecular energy level broadening and shifting occurs for porphyrin molecules when coupled with the metal electrodes, and this level broadening and shifting plays an important role in the electron transport through molecular junctions. Secondly, by carrying out an in-situ deprotection of the acetyl-protected free base porphyrin molecules, it is found out that the presence of acetyl groups reduces the conductance. Thirdly, by incorporating the Matrix-assisted laser desorption/ionization (MALDI) spectrum and the in-situ deprotection prior to formation of molecular junctions, it allows a more precise understanding of the molecules involved in the formation of molecular junctions, and therefore allows an accurate analysis of the conductance histogram. The molecules are prepared by self-assembly and the junctions are formed using a Scanning Tunneling Microscopy (STM) molecular break junction technique. The porphyrin molecules are characterized by MALDI in solution before self-assembly to a gold/mica substrate. The self-assembled monolayers (SAMs) of porphyrins on gold are characterized by Ultraviolet-visible (UV-Vis) reflection spectroscopy to confirm that the molecules are attached to the substrate. The SAMs are then characterized by Angle-Resolved X-ray photoelectron spectroscopy (ARXPS) to determine the thickness and the average molecular orientation of the molecular layer. The electron transport is measured by conductance-displacement (G-S) experiments under a given bias (-0.4V). The conductance value of a single molecule is identified by a statistical analysis over a large set of measurements. In this thesis, I focus on two factors that would affect the electron transport through the porphyrin molecules, namely, the metal ion center, and the deprotection of the end groups. The effect of metal ion center is studied by comparing the conductance of an iron (III) porphyrin (protected) to that of a free base porphyrin (protected). The in-situ deprotection of the molecules before forming the junctions is completed to study the effect of the molecular-electrode interaction. The first factor studied, that is, the metal ion center in the porphyrin molecule, show that the conductance for iron (III) porphyrin (protected) is 3.74 x10-5 G0, and the conductance for the free base porphyrin (protected) is 4.73x10-5 G0 , where G0 = e2 / pih = (25.8kO)-1 is the quantized unit of electrical conductance. Through our collaborative efforts, first principles calculations carried out by our collaborators for the molecular levels of an isolated molecule (without electrodes) show that the energy levels of an iron (III) porphyrin molecule are slightly shifted compared to that of the free base porphyrin. For the free base porphyrin, the highest occupied molecular orbital (HOMO) level (-4.952 eV) lies between the chemical potentials of the substrate (-4.7 eV) and the STM tip (-5.1 eV). This level serves as a channel for electron transport. For the iron (III) porphyrin, the HOMO is at -5.306 eV, which is not in between the chemical potentials of the substrate. Therefore, a significantly smaller conductance is expected for the iron (III) porphyrin compared to the conductance of a free base porphyrin, because of the lack of the electron transport channel. However, the conductance measured from G-S experiments is comparable, i.e. 3.74 x10-5 G0 for iron (III) porphyrin and 4.73x10-5 G0 for free base porphyrin. This suggests that the molecular energy level broadening and shifting occurs for porphyrin molecules when coupled with the metal electrodes, and this level broadening and shifting may significantly affect the electron transport through molecular junctions. The second factor studied, that is, the deprotection of the porphyrin end groups (acetylthio, -SCOCH3), was completed in-situ for the free base porphyrin through the reaction of the acetylthio with sulfuric acid at 35° Celsius for 3 hours. MALDI spectroscopy confirms that two additional deprotected porphyrin species are formed by deprotection, with protonated (MH+) molecular masses of 721 and 679, corresponding to a partially deprotected porphyrin (i.e. only one of the two end groups deprotected), and a fully deprotected porphyrin molecule. Along with the un-reacted acetyl protected porphyrin, a total of 3 porphyrin species are in the solution. This solution is used for self-assembly on a gold/mica surface. The thickness of the in-situ deprotected SAM is determined to be ˜1.7 nm, confirming a relatively upright molecular orientation (54.0°-63.5° between the substrate surface and the molecule), compared to a thickness of ˜1.5 nm for the protected SAM that has a more flat-lying molecular orientation (˜45.6° between the substrate surface and the molecule). From G-S measurements on SAMs prepared by in-situ deprotection, junctions with lower conductance steps at mid 10-5 G0 and junctions with higher conductance steps around 10-4 G 0 are observed. Supported by computational modeling from our collaborating research group, we associate the lower conductance steps to junctions based on the protected form of thiols at the tip-molecule interface, and the higher conductance steps to the deprotected form of the thiol contacts. We suggest that the reduced conductance in the protected porphyrin originates from the presence of the acetyl end groups (-COCH3), rather than from the elongation of the sulfur-gold (S-Au) bonds at the tip-molecule interface. By studying these two factors, I expect this work to provide insights into electron transport through molecules or metal-molecule-metal junctions, and in applications related to integrating molecules as functional units in electronic devices. Future work related to this thesis may include the molecular conductance based on reduction-oxidation (redox) properties of iron ligated porphyrins for the application of molecular switches and molecular memory elements.

A single center retrospective cohort study comparing low-molecular-weight heparins to direct oral anticoagulants for the treatment of venous thromboembolism in patients with cancer - A real world experience.

PubMed

Phelps, Megan K; Wiczer, Tracy E; Erdeljac, H Paige; Van Deusen, Kelsey R; Porter, Kyle; Philips, Gary; Wang, Tzu-Fei

2018-01-01

Introduction Low-molecular-weight heparins are the standard treatment for cancer-associated thrombosis. Recently, direct oral anticoagulants are a new option for thrombosis treatment; however, data supporting the use of direct oral anticoagulants for cancer-associated thrombosis are limited. Objectives The primary objective of this study was to determine the rate of recurrent cancer-associated thrombosis and major bleeding within 6 months of starting either low-molecular-weight heparin or direct oral anticoagulant for treatment of cancer-associated thrombosis. Secondary objectives were to determine the rates of clinically relevant-non-major bleeding and all-cause mortality. Patients/methods This is a retrospective cohort study including adults with cancer-associated thrombosis treated with low-molecular-weight heparin or direct oral anticoagulant between 2010 and 2016 at the Ohio State University. Medical records were reviewed for 6 months after initiation of anticoagulation or until the occurrence of recurrent cancer-associated thrombosis, major bleeding, cessation of anticoagulation of interest, or death, whichever occurred first. Results Four hundred and eighty patients were included (290 low-molecular-weight heparin and 190 direct oral anticoagulant). Patients treated with direct oral anticoagulant were found to carry "lower risk" features including cancer with lower VTE risk and lower rate of metastatic disease. After adjustment for baseline differences, there was no significant difference in the rate of recurrent cancer-associated thrombosis (7.2% low-molecular-weight heparin vs 6.3% direct oral anticoagulant, p = 0.71) or major bleeding (7.6% low-molecular-weight heparin vs 2.6% direct oral anticoagulant, p = 0.08). Conclusions Our study demonstrates that in a select population of cancer patients with VTE, direct oral anticoagulant use can be as effective and safe compared to the standard therapy with low-molecular-weight heparin.

Theory of attosecond delays in molecular photoionization.

PubMed

Baykusheva, Denitsa; Wörner, Hans Jakob

2017-03-28

We present a theoretical formalism for the calculation of attosecond delays in molecular photoionization. It is shown how delays relevant to one-photon-ionization, also known as Eisenbud-Wigner-Smith delays, can be obtained from the complex dipole matrix elements provided by molecular quantum scattering theory. These results are used to derive formulae for the delays measured by two-photon attosecond interferometry based on an attosecond pulse train and a dressing femtosecond infrared pulse. These effective delays are first expressed in the molecular frame where maximal information about the molecular photoionization dynamics is available. The effects of averaging over the emission direction of the electron and the molecular orientation are introduced analytically. We illustrate this general formalism for the case of two polyatomic molecules. N 2 O serves as an example of a polar linear molecule characterized by complex photoionization dynamics resulting from the presence of molecular shape resonances. H 2 O illustrates the case of a non-linear molecule with comparably simple photoionization dynamics resulting from a flat continuum. Our theory establishes the foundation for interpreting measurements of the photoionization dynamics of all molecules by attosecond metrology.

Interactive Molecular Graphics for Augmented Reality Using HoloLens.

PubMed

Müller, Christoph; Krone, Michael; Huber, Markus; Biener, Verena; Herr, Dominik; Koch, Steffen; Reina, Guido; Weiskopf, Daniel; Ertl, Thomas

2018-06-13

Immersive technologies like stereo rendering, virtual reality, or augmented reality (AR) are often used in the field of molecular visualisation. Modern, comparably lightweight and affordable AR headsets like Microsoft's HoloLens open up new possibilities for immersive analytics in molecular visualisation. A crucial factor for a comprehensive analysis of molecular data in AR is the rendering speed. HoloLens, however, has limited hardware capabilities due to requirements like battery life, fanless cooling and weight. Consequently, insights from best practises for powerful desktop hardware may not be transferable. Therefore, we evaluate the capabilities of the HoloLens hardware for modern, GPU-enabled, high-quality rendering methods for the space-filling model commonly used in molecular visualisation. We also assess the scalability for large molecular data sets. Based on the results, we discuss ideas and possibilities for immersive molecular analytics. Besides more obvious benefits like the stereoscopic rendering offered by the device, this specifically includes natural user interfaces that use physical navigation instead of the traditional virtual one. Furthermore, we consider different scenarios for such an immersive system, ranging from educational use to collaborative scenarios.

Development of a Submillimeter Multipass Spectrometer for the Study of Molecular Ions

NASA Astrophysics Data System (ADS)

Carroll, A.; Rocher, B.; Laas, J. C.; Deprince, B. A.; Hays, B.; Weaver, S. L. Widicus; Lang, S.

2012-06-01

We have developed a multipass spectrometer for the submillimeter spectral region that is being used to study molecular ions through gas phase spectroscopy. The optical configuration is based on the design of Perry and coworkers that was implemented in the optical regime. To our knowledge, this is the first implementation of this optical configuration at long wavelengths. The setup involves two nearly concentric spherical mirrors that focus the multiple beam passes into a small area, or ``waist'', in the middle of the sample chamber. A supersonic molecular beam is coupled to the setup so that the molecular beam crosses the optical path at the waist. Initial studies have focused on neutral test molecules to probe the physical properties of the molecular beam under various arrangements of the molecular source relative to the optical path. Current studies focus on coupling a plasma discharge source to the setup to enable the study of molecular ions. Here we present the design of this instrument, compare the spectrometer capabilities to a traditional single pass spectrometer, and discuss the results of initial spectroscopic studies.

Highly Conductive Ionic-Liquid Gels Prepared with Orthogonal Double Networks of a Low-Molecular-Weight Gelator and Cross-Linked Polymer.

PubMed

Kataoka, Toshikazu; Ishioka, Yumi; Mizuhata, Minoru; Minami, Hideto; Maruyama, Tatsuo

2015-10-21

We prepared a heterogeneous double-network (DN) ionogel containing a low-molecular-weight gelator network and a polymer network that can exhibit high ionic conductivity and high mechanical strength. An imidazolium-based ionic liquid was first gelated by the molecular self-assembly of a low-molecular-weight gelator (benzenetricarboxamide derivative), and methyl methacrylate was polymerized with a cross-linker to form a cross-linked poly(methyl methacrylate) (PMMA) network within the ionogel. Microscopic observation and calorimetric measurement revealed that the fibrous network of the low-molecular-weight gelator was maintained in the DN ionogel. The PMMA network strengthened the ionogel of the low-molecular-weight gelator and allowed us to handle the ionogel using tweezers. The orthogonal DNs produced ionogels with a broad range of storage elastic moduli. DN ionogels with low PMMA concentrations exhibited high ionic conductivity that was comparable to that of a neat ionic liquid. The present study demonstrates that the ionic conductivities of the DN and single-network, low-molecular-weight gelator or polymer ionogels strongly depended on their storage elastic moduli.

Effective Brownian ratchet separation by a combination of molecular filtering and a self-spreading lipid bilayer system.

PubMed

Motegi, Toshinori; Nabika, Hideki; Fu, Yingqiang; Chen, Lili; Sun, Yinlu; Zhao, Jianwei; Murakoshi, Kei

2014-07-01

A new molecular manipulation method in the self-spreading lipid bilayer membrane by combining Brownian ratchet and molecular filtering effects is reported. The newly designed ratchet obstacle was developed to effectively separate dye-lipid molecules. The self-spreading lipid bilayer acted as both a molecular transport system and a manipulation medium. By controlling the size and shape of ratchet obstacles, we achieved a significant increase in the separation angle for dye-lipid molecules compared to that with the previous ratchet obstacle. A clear difference was observed between the experimental results and the simple random walk simulation that takes into consideration only the geometrical effect of the ratchet obstacles. This difference was explained by considering an obstacle-dependent local decrease in molecular diffusivity near the obstacles, known as the molecular filtering effect at nanospace. Our experimental findings open up a novel controlling factor in the Brownian ratchet manipulation that allow the efficient separation of molecules in the lipid bilayer based on the combination of Brownian ratchet and molecular filtering effects.

Molecular approaches to solar energy conversion: the energetic cost of charge separation from molecular-excited states.

PubMed

Durrant, James R

2013-08-13

This review starts with a brief overview of the technological potential of molecular-based solar cell technologies. It then goes on to focus on the core scientific challenge associated with using molecular light-absorbing materials for solar energy conversion, namely the separation of short-lived, molecular-excited states into sufficiently long-lived, energetic, separated charges capable of generating an external photocurrent. Comparisons are made between different molecular-based solar cell technologies, with particular focus on the function of dye-sensitized photoelectrochemical solar cells as well as parallels with the function of photosynthetic reaction centres. The core theme of this review is that generating charge carriers with sufficient lifetime and a high quantum yield from molecular-excited states comes at a significant energetic cost-such that the energy stored in these charge-separated states is typically substantially less than the energy of the initially generated excited state. The role of this energetic loss in limiting the efficiency of solar energy conversion by such devices is emphasized, and strategies to minimize this energy loss are compared and contrasted.

Molecular evolution: concepts and the origin of disciplines.

PubMed

Suárez-Díaz, Edna

2009-03-01

This paper focuses on the consolidation of Molecular Evolution, a field originating in the 1960s at the interface of molecular biology, biochemistry, evolutionary biology, biophysics and studies on the origin of life and exobiology. The claim is made that Molecular Evolution became a discipline by integrating different sorts of scientific traditions: experimental, theoretical and comparative. The author critically incorporates Timothy Lenoir's treatment of disciplines (1997), as well as ideas developed by Stephen Toulmin (1962) on the same subject. On their account disciplines are spaces where the social and epistemic dimensions of science are deeply and complexly interwoven. However, a more detailed account of discipline formation and the dynamics of an emerging disciplinary field is lacking in their analysis. The present essay suggests focusing on the role of scientific concepts in the double configuration of disciplines: the social/political and the epistemic order. In the case of Molecular Evolution the concepts of molecular clock and informational molecules played a central role, both in differentiating molecular from classical evolutionists, and in promoting communication between the different sorts of traditions integrated in Molecular Evolution. The paper finishes with a reflection on the historicity of disciplines, and the historicity of our concepts of disciplines.

Accounting for intra-molecular vibrational modes in open quantum system description of molecular systems.

PubMed

Roden, Jan; Strunz, Walter T; Whaley, K Birgitta; Eisfeld, Alexander

2012-11-28

Electronic-vibrational dynamics in molecular systems that interact with an environment involve a large number of degrees of freedom and are therefore often described by means of open quantum system approaches. A popular approach is to include only the electronic degrees of freedom into the system part and to couple these to a non-Markovian bath of harmonic vibrational modes that is characterized by a spectral density. Since this bath represents both intra-molecular and external vibrations, it is important to understand how to construct a spectral density that accounts for intra-molecular vibrational modes that couple further to other modes. Here, we address this problem by explicitly incorporating an intra-molecular vibrational mode together with the electronic degrees of freedom into the system part and using the Fano theory for a resonance coupled to a continuum to derive an "effective" bath spectral density, which describes the contribution of intra-molecular modes. We compare this effective model for the intra-molecular mode with the method of pseudomodes, a widely used approach in simulation of non-Markovian dynamics. We clarify the difference between these two approaches and demonstrate that the respective resulting dynamics and optical spectra can be very different.

Functional Comparison for Lipid Metabolism and Intestinal and Fecal Microflora Enzyme Activities between Low Molecular Weight Chitosan and Chitosan Oligosaccharide in High-Fat-Diet-Fed Rats.

PubMed

Chiu, Chen-Yuan; Feng, Shih-An; Liu, Shing-Hwa; Chiang, Meng-Tsan

2017-07-24

The present study investigated and compared the regulatory effects on the lipid-related metabolism and intestinal disaccharidase/fecal bacterial enzyme activities between low molecular weight chitosan and chitosan oligosaccharide in high-fat-diet-fed rats. Diet supplementation of low molecular weight chitosan showed greater efficiency than chitosan oligosaccharide in suppressing the increased weights in body and in liver and adipose tissues of high-fat-diet-fed rats. Supplementation of low molecular weight chitosan also showed a greater improvement than chitosan oligosaccharide in imbalance of plasma, hepatic, and fecal lipid profiles, and intestinal disaccharidase activities in high-fat-diet-fed rats. Moreover, both low molecular weight chitosan and chitosan oligosaccharide significantly decreased the fecal microflora mucinase and β-glucuronidase activities in high-fat-diet-fed rats. These results suggest that low molecular weight chitosan exerts a greater positive improvement than chitosan oligosaccharide in lipid metabolism and intestinal disaccharidase activity in high-fat-diet-induced obese rats.

Vibrational spectroscopic, molecular docking and quantum chemical studies on 6-aminonicotinamide

NASA Astrophysics Data System (ADS)

Mohamed Asath, R.; Premkumar, S.; Mathavan, T.; Milton Franklin Benial, A.

2017-04-01

The most stable molecular structure of 6-aminonicotinamide (ANA) molecule was predicted by conformational analysis and vibrational spectral analysis was carried out by experimental and theoretical methods. The calculated and experimentally observed vibrational frequencies were assigned and compared. The π→π* electronic transition of the molecule was predicted by theoretically calculated ultraviolet-visible spectra in gas and liquid phase and further validated experimentally using ethanol as a solvent. Frontier molecular orbitals analysis was carried out to probe the reactive nature of the ANA molecule and further the site selectivity to specific chemical reactions were effectively analyzed by Fukui function calculation. The molecular electrostatic potential surface was simulated to confirm the reactive sites of the molecule. The natural bond orbital analysis was also performed to understand the intra molecular interactions, which confirms the bioactivity of the ANA molecule. Neuroprotective nature of the ANA molecule was analyzed by molecular docking analysis and the ANA molecule was identified as a good inhibitor against Alzheimer's disease.

Two dimensional molecular electronics spectroscopy for molecular fingerprinting, DNA sequencing, and cancerous DNA recognition.

PubMed

Rajan, Arunkumar Chitteth; Rezapour, Mohammad Reza; Yun, Jeonghun; Cho, Yeonchoo; Cho, Woo Jong; Min, Seung Kyu; Lee, Geunsik; Kim, Kwang S

2014-02-25

Laser-driven molecular spectroscopy of low spatial resolution is widely used, while electronic current-driven molecular spectroscopy of atomic scale resolution has been limited because currents provide only minimal information. However, electron transmission of a graphene nanoribbon on which a molecule is adsorbed shows molecular fingerprints of Fano resonances, i.e., characteristic features of frontier orbitals and conformations of physisorbed molecules. Utilizing these resonance profiles, here we demonstrate two-dimensional molecular electronics spectroscopy (2D MES). The differential conductance with respect to bias and gate voltages not only distinguishes different types of nucleobases for DNA sequencing but also recognizes methylated nucleobases which could be related to cancerous cell growth. This 2D MES could open an exciting field to recognize single molecule signatures at atomic resolution. The advantages of the 2D MES over the one-dimensional (1D) current analysis can be comparable to those of 2D NMR over 1D NMR analysis.

Studies on molecular structure, vibrational spectra and molecular docking analysis of 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate.

PubMed

Suresh, D M; Amalanathan, M; Joe, I Hubert; Jothy, V Bena; Diao, Yun-Peng

2014-09-15

The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule. Copyright © 2014 Elsevier B.V. All rights reserved.

Detection of DNA damage by using hairpin molecular beacon probes and graphene oxide.

PubMed

Zhou, Jie; Lu, Qian; Tong, Ying; Wei, Wei; Liu, Songqin

2012-09-15

A hairpin molecular beacon tagged with carboxyfluorescein in combination with graphene oxide as a quencher reagent was used to detect the DNA damage by chemical reagents. The fluorescence of molecular beacon was quenched sharply by graphene oxide; while in the presence of its complementary DNA the quenching efficiency decreased because their hybridization prevented the strong adsorbability of molecular beacon on graphene oxide. If the complementary DNA was damaged by a chemical reagent and could not form intact duplex structure with molecular beacon, more molecular beacon would adsorb on graphene oxide increasing the quenching efficiency. Thus, damaged DNA could be detected based on different quenching efficiencies afforded by damaged and intact complementary DNA. The damage effects of chlorpyrifos-methyl and three metabolites of styrene such as mandelieaeids, phenylglyoxylieaeids and epoxystyrene on DNA were studied as models. The method for detection of DNA damage was reliable, rapid and simple compared to the biological methods. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular evolutionary rates are not correlated with temperature and latitude in Squamata: an exception to the metabolic theory of ecology?

PubMed

Rolland, Jonathan; Loiseau, Oriane; Romiguier, Jonathan; Salamin, Nicolas

2016-05-20

The metabolic theory of ecology stipulates that molecular evolutionary rates should correlate with temperature and latitude in ectothermic organisms. Previous studies have shown that most groups of vertebrates, such as amphibians, turtles and even endothermic mammals, have higher molecular evolutionary rates in regions where temperature is high. However, the association between molecular evolutionary rates and temperature or latitude has never been tested in Squamata. We used a large dataset including the spatial distributions and environmental variables for 1,651 species of Squamata and compared the contrast of the rates of molecular evolution with the contrast of temperature and latitude between sister species. Using major axis regressions and a new algorithm to choose independent sister species pairs, we found that temperature and absolute latitude were not associated with molecular evolutionary rates. This absence of association in such a diverse ectothermic group questions the mechanisms explaining current pattern of species diversity in Squamata and challenges the presupposed universality of the metabolic theory of ecology.

Molecular effective coverage surface area of optical clearing agents for predicting optical clearing potential

NASA Astrophysics Data System (ADS)

Feng, Wei; Ma, Ning; Zhu, Dan

2015-03-01

The improvement of methods for optical clearing agent prediction exerts an important impact on tissue optical clearing technique. The molecular dynamic simulation is one of the most convincing and simplest approaches to predict the optical clearing potential of agents by analyzing the hydrogen bonds, hydrogen bridges and hydrogen bridges type forming between agents and collagen. However, the above analysis methods still suffer from some problem such as analysis of cyclic molecule by reason of molecular conformation. In this study, a molecular effective coverage surface area based on the molecular dynamic simulation was proposed to predict the potential of optical clearing agents. Several typical cyclic molecules, fructose, glucose and chain molecules, sorbitol, xylitol were analyzed by calculating their molecular effective coverage surface area, hydrogen bonds, hydrogen bridges and hydrogen bridges type, respectively. In order to verify this analysis methods, in vitro skin samples optical clearing efficacy were measured after 25 min immersing in the solutions, fructose, glucose, sorbitol and xylitol at concentration of 3.5 M using 1951 USAF resolution test target. The experimental results show accordance with prediction of molecular effective coverage surface area. Further to compare molecular effective coverage surface area with other parameters, it can show that molecular effective coverage surface area has a better performance in predicting OCP of agents.

Molecular ways to nanoscale particles and films

NASA Astrophysics Data System (ADS)

Shen, H.; Mathur, S.

2002-06-01

Chemical routes for the synthesis of nanoparticles and films are proving to be highly efficient and versatile in tailoring the elemental combination and intrinsic properties of the target materials. The use of molecular compounds allows a controlled interaction of atoms or molecules, when compared to the solid-state methods, resulting in the formation of compositionally homogeneous deposits or uniform solid particles. Assembling all the elements forming the material in a single molecular compound, the so-called single-source approach augments the formation of nanocrystalline phases at low temperatures with atomically precise structures. To this end, we have shown that predefined reaction (decomposition) chemistry of precursors enforces a molecular level homogeneity in the obtained materials. Following the single-step conversions of appropriate molecular sources, we have obtained films and nanoparticles of oxides (Fe3O4, BaTiO3, ZnAl2O4, CoAl2O4), metal/oxide composites (Ge/GeO2) and ceramic-ceramic composites (LnAIO3/AI2O3; Ln = Pr, Nd). For a comparative evaluation, CoAl2O4 nanoparticles were prepared by both single- and multi-component routes; whereas the single-source approach yielded monophasic high purity spinels, phase contamination, due to monometal phases, was observed in the ceramic obtained from multicomponent mixture. An account of the size-controlled synthesis and characterisation of the new ceramics and composites is presented.

Insight into the molecular mechanism of the sulfur oxidation process by reverse sulfite reductase (rSiR) from sulfur oxidizer Allochromatium vinosum.

PubMed

Ghosh, Semanti; Bagchi, Angshuman

2018-04-26

Sulfur metabolism is one of the oldest known biochemical processes. Chemotrophic or phototrophic proteobacteria, through the dissimilatory pathway, use sulfate, sulfide, sulfite, thiosulfate or elementary sulfur by either reductive or oxidative mechanisms. During anoxygenic photosynthesis, anaerobic sulfur oxidizer Allochromatium vinosum forms sulfur globules that are further oxidized by dsr operon. One of the key redox enzymes in reductive or oxidative sulfur metabolic pathways is the DsrAB protein complex. However, there are practically no reports to elucidate the molecular mechanism of the sulfur oxidation process by the DsrAB protein complex from sulfur oxidizer Allochromatium vinosum. In the present context, we tried to analyze the structural details of the DsrAB protein complex from sulfur oxidizer Allochromatium vinosum by molecular dynamics simulations. The molecular dynamics simulation results revealed the various types of molecular interactions between DsrA and DsrB proteins during the formation of DsrAB protein complex. We, for the first time, predicted the mode of binding interactions between the co-factor and DsrAB protein complex from Allochromatium vinosum. We also compared the binding interfaces of DsrAB from sulfur oxidizer Allochromatium vinosum and sulfate reducer Desulfovibrio vulgaris. This study is the first to provide a comparative aspect of binding modes of sulfur oxidizer Allochromatium vinosum and sulfate reducer Desulfovibrio vulgaris.

A trimeric structural fusion of an antagonistic tumor necrosis factor-α mutant enhances molecular stability and enables facile modification.

PubMed

Inoue, Masaki; Ando, Daisuke; Kamada, Haruhiko; Taki, Shintaro; Niiyama, Mayumi; Mukai, Yohei; Tadokoro, Takashi; Maenaka, Katsumi; Nakayama, Taisuke; Kado, Yuji; Inoue, Tsuyoshi; Tsutsumi, Yasuo; Tsunoda, Shin-Ichi

2017-04-21

Tumor necrosis factor-α (TNF) exerts its biological effect through two types of receptors, p55 TNF receptor (TNFR1) and p75 TNF receptor (TNFR2). An inflammatory response is known to be induced mainly by TNFR1, whereas an anti-inflammatory reaction is thought to be mediated by TNFR2 in some autoimmune diseases. We have been investigating the use of an antagonistic TNF mutant (TNFR1-selective antagonistic TNF mutant (R1antTNF)) to reveal the pharmacological effect of TNFR1-selective inhibition as a new therapeutic modality. Here, we aimed to further improve and optimize the activity and behavior of this mutant protein both in vitro and in vivo Specifically, we examined a trimeric structural fusion of R1antTNF, formed via the introduction of short peptide linkers, as a strategy to enhance bioactivity and molecular stability. By comparative analysis with R1antTNF, the trimeric fusion, referred to as single-chain R1antTNF (scR1antTNF), was found to retain in vitro molecular properties of receptor selectivity and antagonistic activity but displayed a marked increase in thermal stability. The residence time of scR1antTNF in vivo was also significantly prolonged. Furthermore, molecular modification using polyethylene glycol (PEG) was easily controlled by limiting the number of reactive sites. Taken together, our findings show that scR1antTNF displays enhanced molecular stability while maintaining biological activity compared with R1antTNF. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Molecular characterization of branched polysaccharides from Tremella fuciformis by asymmetrical flow field-flow fractionation and size exclusion chromatography.

PubMed

Wu, Ding-Tao; Deng, Yong; Zhao, Jing; Li, Shao-Ping

2017-11-01

To accurately characterize branched polysaccharides with high molecular weights from medicinal and edible mushrooms and identify the limitations of size exclusion chromatography, molecular characteristics of polysaccharides from Tremella fuciformis were determined and compared by asymmetrical flow field-flow fractionation coupled with multiangle laser light scattering and refractive index detection, and size exclusion chromatography coupled with multiangle laser light scattering and refractive index detection, respectively. Results showed that molecular weights of three batches of T. fuciformis polysaccharides were determined as 2.167 × 10 6 (TF1), 2.334 × 10 6 (TF2), and 2.435 × 10 6  Da (TF3) by size exclusion chromatography, and 3.432 × 10 6 (TF1), 3.739 × 10 6 (TF2), and 3.742 × 10 6  Da (TF3) by asymmetrical flow field-flow fractionation, as well as 3.469 × 10 6  Da (TF1) by off-line multiangle laser light scattering, respectively. Results suggested that size exclusion chromatography was unable to accurately characterize T. fuciformis polysaccharides, which may be due to its limitations such as shear degradation and abnormal coelution. Compared to size exclusion chromatography, asymmetrical flow field-flow fractionation could be a better technique for the molecular characterization of branched polysaccharides with high molecular weights from medicinal and edible mushrooms, as well as from other natural resources. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparative Transcriptomic Exploration Reveals Unique Molecular Adaptations of Neuropathogenic Trichobilharzia to Invade and Parasitize Its Avian Definitive Host

PubMed Central

Leontovyč, Roman; Young, Neil D.; Korhonen, Pasi K.; Hall, Ross S.; Tan, Patrick; Mikeš, Libor; Kašný, Martin; Horák, Petr; Gasser, Robin B.

2016-01-01

To date, most molecular investigations of schistosomatids have focused principally on blood flukes (schistosomes) of humans. Despite the clinical importance of cercarial dermatitis in humans caused by Trichobilharzia regenti and the serious neuropathologic disease that this parasite causes in its permissive avian hosts and accidental mammalian hosts, almost nothing is known about the molecular aspects of how this fluke invades its hosts, migrates in host tissues and how it interacts with its hosts’ immune system. Here, we explored selected aspects using a transcriptomic-bioinformatic approach. To do this, we sequenced, assembled and annotated the transcriptome representing two consecutive life stages (cercariae and schistosomula) of T. regenti involved in the first phases of infection of the avian host. We identified key biological and metabolic pathways specific to each of these two developmental stages and also undertook comparative analyses using data available for taxonomically related blood flukes of the genus Schistosoma. Detailed comparative analyses revealed the unique involvement of carbohydrate metabolism, translation and amino acid metabolism, and calcium in T. regenti cercariae during their invasion and in growth and development, as well as the roles of cell adhesion molecules, microaerobic metabolism (citrate cycle and oxidative phosphorylation), peptidases (cathepsins) and other histolytic and lysozomal proteins in schistosomula during their particular migration in neural tissues of the avian host. In conclusion, the present transcriptomic exploration provides new and significant insights into the molecular biology of T. regenti, which should underpin future genomic and proteomic investigations of T. regenti and, importantly, provides a useful starting point for a range of comparative studies of schistosomatids and other trematodes. PMID:26863542

Molecular Subtypes of Breast Cancer: Long-term Incidence Trends and Prognostic Differences.

PubMed

Valla, Marit; Vatten, Lars Johan; Engstrøm, Monica Jernberg; Haugen, Olav Anton; Akslen, Lars Andreas; Bjørngaard, Johan Håkon; Hagen, Anne Irene; Ytterhus, Borgny; Bofin, Anna Mary; Opdahl, Signe

2016-12-01

Secular trends in incidence and prognosis of molecular breast cancer subtypes are poorly described. We studied long-term trends in a population of Norwegian women born 1886-1977. A total of 52,949 women were followed for breast cancer incidence, and 1,423 tumors were reclassified into molecular subtypes using IHC and in situ hybridization. We compared incidence rates among women born 1886-1928 and 1929-1977, estimated age-specific incidence rate ratios (IRR), and performed multiple imputations to account for unknown subtype. Prognosis was compared for women diagnosed before 1995 and in 1995 or later, estimating cumulative risk of death and HRs. Between 50 and 69 years of age, incidence rates of Luminal A and Luminal B (HER2 - ) were higher among women born in 1929 or later, compared with before 1929 [IRRs 50-54 years; after imputations: 3.5; 95% confidence interval (CI), 1.8-6.9 and 2.5; 95% CI, 1.2-5.2, respectively], with no clear differences for other subtypes. Rates of death were lower in women diagnosed in 1995 or later, compared to before 1995, for Luminal A (HR 0.4; 95% CI, 0.3-0.5), Luminal B (HER2 - ; HR 0.5; 95% CI, 0.3-0.7), and Basal phenotype (HR 0.4; 95% CI, 0.2-0.9). We found a strong secular incidence increase restricted to Luminal A and Luminal B (HER2 - ) subtypes, combined with a markedly improved prognosis for these subtypes and for the Basal phenotype. This study documents a clear secular increase in incidence and a concomitant improved prognosis for specific molecular breast cancer subtypes. Cancer Epidemiol Biomarkers Prev; 25(12); 1625-34. ©2016 AACR. ©2016 American Association for Cancer Research.

Porcine sclera as a model of human sclera for in vitro transport experiments: histology, SEM, and comparative permeability

PubMed Central

Ferrari, G.; Quarta, M.; Macaluso, C.; Govoni, P.; Dallatana, D.; Santi, P.

2009-01-01

Purpose To evaluate porcine sclera as a model of human sclera for in vitro studies of transscleral drug delivery of both low and high molecular weight compounds. Methods Human and porcine scleras were characterized for thickness and water content. The tissue surface was examined by scanning electron microscopy (SEM), and the histology was studied with hematoxylin-eosin staining. Comparative permeation experiments were performed using three model molecules, acetaminophen as the model compound for small molecules; a linear dextran with a molecular weight of 120 kDa as the model compound for high molecular weight drugs; and insulin, which was chosen as the model protein. Permeation parameters such as flux, lag time, and permeability coefficient were determined and compared. Results Human and porcine scleras have a similar histology and collagen bundle organization. The water content is approx 70% for both tissues while a statistically significant difference was found for the thickness, porcine sclera being approximately twofold thicker than human sclera. Differences in thickness produced differences in the permeability coefficient. In fact, human sclera was found to be two to threefold more permeable toward the three molecules studied than porcine sclera. Conclusions The results obtained in the present paper prove that porcine sclera can be considered a good model for human sclera for in vitro permeation experiments of both low and high molecular weight compounds. In fact, if the different tissue thickness is taken into account, comparable permeability was demonstrated. This suggests a possible use of this model in the evaluation of the transscleral permeation of new biotech compounds, which currently represent the most innovative and efficient therapeutic options for the treatment of ocular diseases. PMID:19190734

Extracellular matrix fragmentation in young, healthy cartilaginous tissues.

PubMed

Craddock, R J; Hodson, N W; Ozols, M; Shearer, T; Hoyland, J A; Sherratt, M J

2018-02-09

Although the composition and structure of cartilaginous tissues is complex, collagen II fibrils and aggrecan are the most abundant assemblies in both articular cartilage (AC) and the nucleus pulposus (NP) of the intervertebral disc (IVD). Whilst structural heterogeneity of intact aggrecan ( containing three globular domains) is well characterised, the extent of aggrecan fragmentation in healthy tissues is poorly defined. Using young, yet skeletally mature (18-30 months), bovine AC and NP tissues, it was shown that, whilst the ultrastructure of intact aggrecan was tissue-dependent, most molecules (AC: 95 %; NP: 99.5 %) were fragmented (lacking one or more globular domains). Fragments were significantly smaller and more structurally heterogeneous in the NP compared with the AC (molecular area; AC: 8543 nm2; NP: 4625 nm2; p < 0.0001). In contrast, fibrillar collagen appeared structurally intact and tissue-invariant. Molecular fragmentation is considered indicative of a pathology; however, these young, skeletally mature tissues were histologically and mechanically (reduced modulus: AC: ≈ 500 kPa; NP: ≈ 80 kPa) comparable to healthy tissues and devoid of notable gelatinase activity (compared with rat dermis). As aggrecan fragmentation was prevalent in neonatal bovine AC (99.5 % fragmented, molecular area: 5137 nm2) as compared with mature AC (95.0 % fragmented, molecular area: 8667 nm2), it was hypothesised that targeted proteolysis might be an adaptive process that modified aggrecan packing (as simulated computationally) and, hence, tissue charge density, mechanical properties and porosity. These observations provided a baseline against which pathological and/or age-related fragmentation of aggrecan could be assessed and suggested that new strategies might be required to engineer constructs that mimic the mechanical properties of native cartilaginous tissues.

Molecular imaging reveals elevated VEGFR-2 expression in retinal capillaries in diabetes: a novel biomarker for early diagnosis

PubMed Central

Sun, Dawei; Nakao, Shintaro; Xie, Fang; Zandi, Souska; Bagheri, Abouzar; Kanavi, Mozhgan Rezaei; Samiei, Shahram; Soheili, Zahra-Soheila; Frimmel, Sonja; Zhang, Zhongyu; Ablonczy, Zsolt; Ahmadieh, Hamid; Hafezi-Moghadam, Ali

2014-01-01

Diabetic retinopathy (DR) is a microvascular complication of diabetes and a leading cause of vision loss. Biomarkers and methods for early diagnosis of DR are urgently needed. Using a new molecular imaging approach, we show up to 94% higher accumulation of custom designed imaging probes against vascular endothelial growth factor receptor 2 (VEGFR-2) in retinal and choroidal vessels of diabetic animals (P<0.01), compared to normal controls. More than 80% of the VEGFR-2 in the diabetic retina was in the capillaries, compared to 47% in normal controls (P<0.01). Angiography in rabbit retinas revealed microvascular capillaries to be the location for VEGF-A-induced leakage, as expressed by significantly higher rate of fluorophore spreading with VEGF-A injection when compared to vehicle control (26±2 vs. 3±1 μm/s, P<0.05). Immunohistochemistry showed VEGFR-2 expression in capillaries of diabetic animals but not in normal controls. Macular vessels from diabetic patients (n=7) showed significantly more VEGFR-2 compared to nondiabetic controls (n=5) or peripheral retinal regions of the same retinas (P<0.01 in both cases). Here we introduce a new approach for early diagnosis of DR and VEGFR-2 as a molecular marker. VEGFR-2 could become a key diagnostic target, one that might help to prevent retinal vascular leakage and proliferation in diabetic patients.—Sun, D., Nakao, S., Xie, F., Zandi, S., Bagheri, A., Kanavi, M. R., Samiei, S., Soheili, Z.-S., Frimmel, S., Zhang, Z., Ablonczy, Z., Ahmadieh, H., Hafezi-Moghadam, A. Molecular imaging reveals elevated VEGFR-2 expression in retinal capillaries in diabetes: a novel biomarker for early diagnosis. PMID:24903276

Porcine sclera as a model of human sclera for in vitro transport experiments: histology, SEM, and comparative permeability.

PubMed

Nicoli, S; Ferrari, G; Quarta, M; Macaluso, C; Govoni, P; Dallatana, D; Santi, P

2009-01-01

To evaluate porcine sclera as a model of human sclera for in vitro studies of transscleral drug delivery of both low and high molecular weight compounds. Human and porcine scleras were characterized for thickness and water content. The tissue surface was examined by scanning electron microscopy (SEM), and the histology was studied with hematoxylin-eosin staining. Comparative permeation experiments were performed using three model molecules, acetaminophen as the model compound for small molecules; a linear dextran with a molecular weight of 120 kDa as the model compound for high molecular weight drugs; and insulin, which was chosen as the model protein. Permeation parameters such as flux, lag time, and permeability coefficient were determined and compared. Human and porcine scleras have a similar histology and collagen bundle organization. The water content is approx 70% for both tissues while a statistically significant difference was found for the thickness, porcine sclera being approximately twofold thicker than human sclera. Differences in thickness produced differences in the permeability coefficient. In fact, human sclera was found to be two to threefold more permeable toward the three molecules studied than porcine sclera. The results obtained in the present paper prove that porcine sclera can be considered a good model for human sclera for in vitro permeation experiments of both low and high molecular weight compounds. In fact, if the different tissue thickness is taken into account, comparable permeability was demonstrated. This suggests a possible use of this model in the evaluation of the transscleral permeation of new biotech compounds, which currently represent the most innovative and efficient therapeutic options for the treatment of ocular diseases.

Real-time fluorescence loop mediated isothermal amplification for the diagnosis of malaria.

PubMed

Lucchi, Naomi W; Demas, Allison; Narayanan, Jothikumar; Sumari, Deborah; Kabanywanyi, Abdunoor; Kachur, S Patrick; Barnwell, John W; Udhayakumar, Venkatachalam

2010-10-29

Molecular diagnostic methods can complement existing tools to improve the diagnosis of malaria. However, they require good laboratory infrastructure thereby restricting their use to reference laboratories and research studies. Therefore, adopting molecular tools for routine use in malaria endemic countries will require simpler molecular platforms. The recently developed loop-mediated isothermal amplification (LAMP) method is relatively simple and can be improved for better use in endemic countries. In this study, we attempted to improve this method for malaria diagnosis by using a simple and portable device capable of performing both the amplification and detection (by fluorescence) of LAMP in one platform. We refer to this as the RealAmp method. Published genus-specific primers were used to test the utility of this method. DNA derived from different species of malaria parasites was used for the initial characterization. Clinical samples of P. falciparum were used to determine the sensitivity and specificity of this system compared to microscopy and a nested PCR method. Additionally, directly boiled parasite preparations were compared with a conventional DNA isolation method. The RealAmp method was found to be simple and allowed real-time detection of DNA amplification. The time to amplification varied but was generally less than 60 minutes. All human-infecting Plasmodium species were detected. The sensitivity and specificity of RealAmp in detecting P. falciparum was 96.7% and 91.7% respectively, compared to microscopy and 98.9% and 100% respectively, compared to a standard nested PCR method. In addition, this method consistently detected P. falciparum from directly boiled blood samples. This RealAmp method has great potential as a field usable molecular tool for diagnosis of malaria. This tool can provide an alternative to conventional PCR based diagnostic methods for field use in clinical and operational programs.

Molecular Analysis of Sarcoidosis Granulomas Reveals Antimicrobial Targets

PubMed Central

Celada, Lindsay J.; Polosukhin, Vasiliy V.; Atkinson, James B.; Drake, Wonder P.

2016-01-01

Sarcoidosis is a granulomatous disease of unknown cause. Prior molecular and immunologic studies have confirmed the presence of mycobacterial virulence factors, such as catalase peroxidase and superoxide dismutase A, within sarcoidosis granulomas. Molecular analysis of granulomas can identify targets of known antibiotics classes. Currently, major antibiotics are directed against DNA synthesis, protein synthesis, and cell wall formation. We conducted molecular analysis of 40 sarcoidosis diagnostic specimens and compared them with 33 disease control specimens for the presence of mycobacterial genes that encode antibiotic targets. We assessed for genes involved in DNA synthesis (DNA gyrase A [gyrA] and DNA gyrase B), protein synthesis (RNA polymerase subunit β), cell wall synthesis (embCAB operon and enoyl reductase), and catalase peroxidase. Immunohistochemical analysis was conducted to investigate the locale of mycobacterial genes such as gyrA within 12 sarcoidosis specimens and 12 disease controls. Mycobacterial DNA was detected in 33 of 39 sarcoidosis specimens by quantitative real-time polymerase chain reaction compared with 2 of 30 disease control specimens (P < 0.001, two-tailed Fisher’s test). Twenty of 39 were positive for three or more mycobacterial genes, compared with 1 of 30 control specimens (P < 0.001, two-tailed Fisher’s test). Immunohistochemistry analysis localized mycobacterial gyrA nucleic acids to sites of granuloma formation in 9 of 12 sarcoidosis specimens compared with 1 of 12 disease controls (P < 0.01). Microbial genes encoding enzymes that can be targeted by currently available antimycobacterial antibiotics are present in sarcoidosis specimens and localize to sites of granulomatous inflammation. Use of antimicrobials directed against target enzymes may be an innovative treatment alternative. PMID:26807608

Molecular markers in pediatric neuro-oncology.

PubMed

Ichimura, Koichi; Nishikawa, Ryo; Matsutani, Masao

2012-09-01

Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment.

Morphological diagnostics of star formation in molecular clouds

NASA Astrophysics Data System (ADS)

Beaumont, Christopher Norris

Molecular clouds are the birth sites of all star formation in the present-day universe. They represent the initial conditions of star formation, and are the primary medium by which stars transfer energy and momentum back to parsec scales. Yet, the physical evolution of molecular clouds remains poorly understood. This is not due to a lack of observational data, nor is it due to an inability to simulate the conditions inside molecular clouds. Instead, the physics and structure of the interstellar medium are sufficiently complex that interpreting molecular cloud data is very difficult. This dissertation mitigates this problem, by developing more sophisticated ways to interpret morphological information in molecular cloud observations and simulations. In particular, I have focused on leveraging machine learning techniques to identify physically meaningful substructures in the interstellar medium, as well as techniques to inter-compare molecular cloud simulations to observations. These contributions make it easier to understand the interplay between molecular clouds and star formation. Specific contributions include: new insight about the sheet-like geometry of molecular clouds based on observations of stellar bubbles; a new algorithm to disambiguate overlapping yet morphologically distinct cloud structures; a new perspective on the relationship between molecular cloud column density distributions and the sizes of cloud substructures; a quantitative analysis of how projection effects affect measurements of cloud properties; and an automatically generated, statistically-calibrated catalog of bubbles identified from their infrared morphologies.

Effects of molecular dissociation on the hydrogen equation of state

NASA Astrophysics Data System (ADS)

Bonev, Stanimir; Schwegler, Eric; Galli, Giulia; Gygi, Francois

2002-03-01

It has been suggested recently(François Gygi and G. Galli, submitted to Phys. Rev. Lett.) that the physical mechanism behind the larger compressibility of liquid deuterium observed in laser shock experiments as compared to ab initio simulations may be related to shock-induced electronic excitations. A possible result of such non-adiabatic processes is hindering of the molecular dissociation. This has motivated us to study the importance of molecular dissociation on the hydrogen equation of state. To this end, we have carried out ab initio molecular dynamics simulations of liquid deuterium where intramolecular dissociation is prevented by the use of bond length contraints. Simulations at both fixed thermodynamic conditions and dynamical simulations of shocked deuterium will be discussed.

A study of physical properties of ODPA-p-PDA polyimide films

NASA Technical Reports Server (NTRS)

Singh, Jag J.; Eftekhari, Abe; St.clair, Terry L.

1990-01-01

Physical properties were investigated of ODPA-p-PDA polyimide films, including their lower molecular weight versions with phthalimide endcaps. Free volume, determined by low energy positron annihilation in the test films, was the major parameter of interest since all other physical properties are ostensibly related to it. It affects the dielectric constant as well as the saturation moisture pickup of the test films. An empirical relation was developed between the free volume and molecular weight of the test films, comparable to the Mark-Houwink relation between the polymer solution viscosity and the molecular weight. Development of such a relation constitutes a unique achievement since it enables researchers to estimate the molecular weight of an intractable polymer in solid state for the first time.

Alternative types of molecule-decorated atomic chains in Au–CO–Au single-molecule junctions

PubMed Central

Balogh, Zoltán; Makk, Péter

2015-01-01

Summary We investigate the formation and evolution of Au–CO single-molecule break junctions. The conductance histogram exhibits two distinct molecular configurations, which are further investigated by a combined statistical analysis. According to conditional histogram and correlation analysis these molecular configurations show strong anticorrelations with each other and with pure Au monoatomic junctions and atomic chains. We identify molecular precursor configurations with somewhat higher conductance, which are formed prior to single-molecule junctions. According to detailed length analysis two distinct types of molecule-affected chain-formation processes are observed, and we compare these results to former theoretical calculations considering bridge- and atop-type molecular configurations where the latter has reduced conductance due to destructive Fano interference. PMID:26199840

Alternative types of molecule-decorated atomic chains in Au-CO-Au single-molecule junctions.

PubMed

Balogh, Zoltán; Makk, Péter; Halbritter, András

2015-01-01

We investigate the formation and evolution of Au-CO single-molecule break junctions. The conductance histogram exhibits two distinct molecular configurations, which are further investigated by a combined statistical analysis. According to conditional histogram and correlation analysis these molecular configurations show strong anticorrelations with each other and with pure Au monoatomic junctions and atomic chains. We identify molecular precursor configurations with somewhat higher conductance, which are formed prior to single-molecule junctions. According to detailed length analysis two distinct types of molecule-affected chain-formation processes are observed, and we compare these results to former theoretical calculations considering bridge- and atop-type molecular configurations where the latter has reduced conductance due to destructive Fano interference.

Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

PubMed

Jiang, Ping; Yaşar, Fatih; Hansmann, Ulrich H E

2013-08-13

We compare the efficiency of multicanonical and replica exchange molecular dynamics for the sampling of folding/unfolding events in simulations of proteins with end-to-end β -sheet. In Go-model simulations of the 75-residue MNK6, we observe improvement factors of 30 in the number of folding/unfolding events of multicanonical molecular dynamics over replica exchange molecular dynamics. As an application, we use this enhanced sampling to study the folding landscape of the 36-residue DS119 with an all-atom physical force field and implicit solvent. Here, we find that the rate-limiting step is the formation of the central helix that then provides a scaffold for the parallel β -sheet formed by the two chain ends.

Comparisons of molecular karyotype and RAPD patterns of anuran trypanosome isolates during long-term in vitro cultivation.

PubMed

Lun, Z R; Desser, S S

1996-01-01

The patterns of random amplified fragments and molecular karyotypes of 12 isolates of anuran trypanosomes continuously cultured in vitro were compared by random amplified polymorphic DNA (RAPD) analysis and pulsed field gradient gel electrophoresis (PFGE). The time interval between preparation of two series of samples was one year. Changes were not observed in the number and size of sharp, amplified fragments of DNA samples from both series examined with the ten primers used. Likewise, changes in the molecular karyotypes were not detected between the two samples of these isolates. These results suggest that the molecular karyotype and the RAPD patterns of the anuran trypanosomes remain stable after being cultured continuously in vitro for one year.

Serious Game Leverages Productive Negativity to Facilitate Conceptual Change in Undergraduate Molecular Biology: A Mixed-Methods Randomized Controlled Trial

ERIC Educational Resources Information Center

Gauthier, Andrea; Jenkinson, Jodie

2017-01-01

We designed a serious game, MolWorlds, to facilitate conceptual change about molecular emergence by using game mechanics (resource management, immersed 3rd person character, sequential level progression, and 3-star scoring system) to encourage cycles of productive negativity. We tested the value-added effect of game design by comparing and…

Molecular and morphological characterization of Xiphinema chambersi population from live oak in Jekyll Island, Georgia, with comments on morphometric variations

Treesearch

Zafar A Handoo; Lynn K. Carta; Andrea M. Skantar; Sergei A. Subbotin; Stephen W. Fraedrich

2016-01-01

A population of Xiphinema chambersi from the root zone around live oak (Quercus virginiana Mill.) trees on Jekyll Island, GA, is described using both morphological and molecular tools and compared with descriptions of type specimens. Initially, because of a few morphological differences, this nematode was thought to represent...

[A comparative immunochemical analysis of allergoids and allergens].

PubMed

Fradkin, V A; Tsvetkov, N V; Diakiv, V V; Lavrenchik, E I

1992-01-01

In comparison with allergens having protein fragments with a molecular weight not exceeding 110 kD, allergoids have been found to consist of larger fragments with a molecular weight of 10-150 kD. Allergoids have less charged components than initial allergens and less antigenic components. Allergoids retain their capacity for stimulating the production of antibodies, specific to all antigenic components.

Molecular structure of sodium lignosulfonate from different sources and their properties as dispersant of TiO2 slurry

Treesearch

Haifeng Zhou; Dongjie Yang; Junyong Zhu

2016-01-01

The molecular structure and properties of four sodium lignosulfates (LSs) derived from pulping or bioethanol production were evaluated and compared. SXP and SAL were produced by sulfite pulping and sulfonation reaction of lignin from alkali pulping of poplar, respectively. LS-180 and LS-150 were from sulfite pretreatment to overcome recalcitrance of lignocelluloses (...

Effect of Bead and Illustrations Models on High School Students' Achievement in Molecular Genetics

ERIC Educational Resources Information Center

Rotbain, Yosi; Marbach-Ad, Gili; Stavy, Ruth

2006-01-01

Our main goal in this study was to explore whether the use of models in molecular genetics instruction in high school can contribute to students' understanding of concepts and processes in genetics. Three comparable groups of 11th and 12th graders participated: The control group (116 students) was taught in the traditional lecture format, while…

HPAM: Hirshfeld Partitioned Atomic Multipoles

PubMed Central

Elking, Dennis M.; Perera, Lalith; Pedersen, Lee G.

2011-01-01

An implementation of the Hirshfeld (HD) and Hirshfeld-Iterated (HD-I) atomic charge density partitioning schemes is described. Atomic charges and atomic multipoles are calculated from the HD and HD-I atomic charge densities for arbitrary atomic multipole rank lmax on molecules of arbitrary shape and size. The HD and HD-I atomic charges/multipoles are tested by comparing molecular multipole moments and the electrostatic potential (ESP) surrounding a molecule with their reference ab initio values. In general, the HD-I atomic charges/multipoles are found to better reproduce ab initio electrostatic properties over HD atomic charges/multipoles. A systematic increase in precision for reproducing ab initio electrostatic properties is demonstrated by increasing the atomic multipole rank from lmax = 0 (atomic charges) to lmax = 4 (atomic hexadecapoles). Both HD and HD-I atomic multipoles up to rank lmax are shown to exactly reproduce ab initio molecular multipole moments of rank L for L ≤ lmax. In addition, molecular dipole moments calculated by HD, HD-I, and ChelpG atomic charges only (lmax = 0) are compared with reference ab initio values. Significant errors in reproducing ab initio molecular dipole moments are found if only HD or HD-I atomic charges used. PMID:22140274

An improved molecular dynamics algorithm to study thermodiffusion in binary hydrocarbon mixtures

NASA Astrophysics Data System (ADS)

Antoun, Sylvie; Saghir, M. Ziad; Srinivasan, Seshasai

2018-03-01

In multicomponent liquid mixtures, the diffusion flow of chemical species can be induced by temperature gradients, which leads to a separation of the constituent components. This cross effect between temperature and concentration is known as thermodiffusion or the Ludwig-Soret effect. The performance of boundary driven non-equilibrium molecular dynamics along with the enhanced heat exchange (eHEX) algorithm was studied by assessing the thermodiffusion process in n-pentane/n-decane (nC5-nC10) binary mixtures. The eHEX algorithm consists of an extended version of the HEX algorithm with an improved energy conservation property. In addition to this, the transferable potentials for phase equilibria-united atom force field were employed in all molecular dynamics (MD) simulations to precisely model the molecular interactions in the fluid. The Soret coefficients of the n-pentane/n-decane (nC5-nC10) mixture for three different compositions (at 300.15 K and 0.1 MPa) were calculated and compared with the experimental data and other MD results available in the literature. Results of our newly employed MD algorithm showed great agreement with experimental data and a better accuracy compared to other MD procedures.

Molecular Isotopic Distribution Analysis (MIDAs) with Adjustable Mass Accuracy

NASA Astrophysics Data System (ADS)

Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo

2014-01-01

In this paper, we present Molecular Isotopic Distribution Analysis (MIDAs), a new software tool designed to compute molecular isotopic distributions with adjustable accuracies. MIDAs offers two algorithms, one polynomial-based and one Fourier-transform-based, both of which compute molecular isotopic distributions accurately and efficiently. The polynomial-based algorithm contains few novel aspects, whereas the Fourier-transform-based algorithm consists mainly of improvements to other existing Fourier-transform-based algorithms. We have benchmarked the performance of the two algorithms implemented in MIDAs with that of eight software packages (BRAIN, Emass, Mercury, Mercury5, NeutronCluster, Qmass, JFC, IC) using a consensus set of benchmark molecules. Under the proposed evaluation criteria, MIDAs's algorithms, JFC, and Emass compute with comparable accuracy the coarse-grained (low-resolution) isotopic distributions and are more accurate than the other software packages. For fine-grained isotopic distributions, we compared IC, MIDAs's polynomial algorithm, and MIDAs's Fourier transform algorithm. Among the three, IC and MIDAs's polynomial algorithm compute isotopic distributions that better resemble their corresponding exact fine-grained (high-resolution) isotopic distributions. MIDAs can be accessed freely through a user-friendly web-interface at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/midas/index.html.

Communication: Localized molecular orbital analysis of the effect of electron correlation on the anomalous isotope effect in the NMR spin-spin coupling constant in methane

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zarycz, M. Natalia C., E-mail: mnzarycz@gmail.com; Provasi, Patricio F., E-mail: patricio@unne.edu.ar; Sauer, Stephan P. A., E-mail: sauer@kiku.dk

2014-10-21

We discuss the effect of electron correlation on the unexpected differential sensitivity (UDS) in the {sup 1}J(C–H) coupling constant of CH{sub 4} using a decomposition into contributions from localized molecular orbitals and compare with the {sup 1}J(N–H) coupling constant in NH{sub 3}. In particular, we discuss the well known fact that uncorrelated coupled Hartree-Fock (CHF) calculations are not able to reproduce the UDS in methane. For this purpose we have implemented for the first time a localized molecular orbital analysis for the second order polarization propagator approximation with coupled cluster singles and doubles amplitudes—SOPPA(CCSD) in the DALTON program. Comparing themore » changes in the localized orbital contributions at the correlated SOPPA and SOPPA(CCSD) levels and at the uncorrelated CHF level, we find that the latter overestimates the effect of stretching the bond between the coupled atoms on the contribution to the coupling from the localized bonding orbital between these atoms. This disturbs the subtle balance between the molecular orbital contributions, which lead to the UDS in methane.« less

Scalable and fast heterogeneous molecular simulation with predictive parallelization schemes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guzman, Horacio V.; Junghans, Christoph; Kremer, Kurt

Multiscale and inhomogeneous molecular systems are challenging topics in the field of molecular simulation. In particular, modeling biological systems in the context of multiscale simulations and exploring material properties are driving a permanent development of new simulation methods and optimization algorithms. In computational terms, those methods require parallelization schemes that make a productive use of computational resources for each simulation and from its genesis. Here, we introduce the heterogeneous domain decomposition approach, which is a combination of an heterogeneity-sensitive spatial domain decomposition with an a priori rearrangement of subdomain walls. Within this approach and paper, the theoretical modeling and scalingmore » laws for the force computation time are proposed and studied as a function of the number of particles and the spatial resolution ratio. We also show the new approach capabilities, by comparing it to both static domain decomposition algorithms and dynamic load-balancing schemes. Specifically, two representative molecular systems have been simulated and compared to the heterogeneous domain decomposition proposed in this work. Finally, these two systems comprise an adaptive resolution simulation of a biomolecule solvated in water and a phase-separated binary Lennard-Jones fluid.« less

Scalable and fast heterogeneous molecular simulation with predictive parallelization schemes

DOE PAGES

Guzman, Horacio V.; Junghans, Christoph; Kremer, Kurt; ...

2017-11-27

Multiscale and inhomogeneous molecular systems are challenging topics in the field of molecular simulation. In particular, modeling biological systems in the context of multiscale simulations and exploring material properties are driving a permanent development of new simulation methods and optimization algorithms. In computational terms, those methods require parallelization schemes that make a productive use of computational resources for each simulation and from its genesis. Here, we introduce the heterogeneous domain decomposition approach, which is a combination of an heterogeneity-sensitive spatial domain decomposition with an a priori rearrangement of subdomain walls. Within this approach and paper, the theoretical modeling and scalingmore » laws for the force computation time are proposed and studied as a function of the number of particles and the spatial resolution ratio. We also show the new approach capabilities, by comparing it to both static domain decomposition algorithms and dynamic load-balancing schemes. Specifically, two representative molecular systems have been simulated and compared to the heterogeneous domain decomposition proposed in this work. Finally, these two systems comprise an adaptive resolution simulation of a biomolecule solvated in water and a phase-separated binary Lennard-Jones fluid.« less

Comparative study of the molecularly imprinted polymers prepared by reversible addition-fragmentation chain transfer "bulk" polymerization and traditional radical "bulk" polymerization.

PubMed

Ma, Yue; Pan, Guoqing; Zhang, Ying; Guo, Xianzhi; Zhang, Huiqi

2013-05-01

Bisphenol A (BPA) and propranolol-imprinted polymers have been prepared via both reversible addition-fragmentation chain transfer "bulk" polymerization (RAFTBP) and traditional radical "bulk" polymerization (TRBP) under similar reaction conditions, and their equilibrium binding properties were compared in detail for the first time. The chemical compositions, specific surface areas, equilibrium bindings, and selectivity of the obtained molecularly imprinted polymers (MIPs) were systematically characterized. The experimental results showed that the MIPs with molecular imprinting effects and quite fast binding kinetics could be readily prepared via RAFTBP, but they did not show improved template binding properties in comparison with those prepared via TRBP, which is in sharp contrast to many previous reports. This could be attributed to the heavily interrupted equilibrium between the dormant species and active radicals in the RAFT mechanism because of the occurrence of fast gelation during RAFTBP. The findings presented here strongly demonstrates that the application of controlled radical polymerizations (CRPs) in molecular imprinting does not always benefit the binding properties of the resultant MIPs, which is of significant importance for the rational use of CRPs in generating MIPs with improved properties. Copyright © 2013 John Wiley & Sons, Ltd.

A comparative analysis of the effectiveness of cytogenetic and molecular genetic methods in the detection of Down syndrome.

PubMed

Mačkić-Đurović, Mirela; Projić, Petar; Ibrulj, Slavka; Cakar, Jasmina; Marjanović, Damir

2014-05-01

The goal of this study was to examine the effectiveness of 6 STR markers application (D21S1435, D21S11, D21S1270, D21S1411, D21S226 and IFNAR) in molecular genetic diagnostics of Down syndrome (DS) and to compare it with cytogenetic method. Testing was performed on 73 children, with the previously cytogenetically confirmed Down syndrome. DNA isolated from the buccal swab was used. Previously mentioned loci located on chromosome 21 were simultaneously amplified using quantitative fluorescence PCR (QF PCR). Using this method, 60 previously cytogenetically diagnosed DS with standard type of trisomy 21 were confirmed. Furthermore, six of eight children with mosaic type of DS were detected. Two false negative results for mosaic type of DS were obtained. Finally, five children with the translocation type of Down syndrome were also confirmed with this molecular test. In conclusion, molecular genetic analysis of STR loci is fast, cheap and simple method that could be used in detection of DS. Regarding possible false results detected for certain number of mosaic types, cytogenetic analysis should be used as a confirmatory test.

Ensemble Sampling vs. Time Sampling in Molecular Dynamics Simulations of Thermal Conductivity

DOE PAGES

Gordiz, Kiarash; Singh, David J.; Henry, Asegun

2015-01-29

In this report we compare time sampling and ensemble averaging as two different methods available for phase space sampling. For the comparison, we calculate thermal conductivities of solid argon and silicon structures, using equilibrium molecular dynamics. We introduce two different schemes for the ensemble averaging approach, and show that both can reduce the total simulation time as compared to time averaging. It is also found that velocity rescaling is an efficient mechanism for phase space exploration. Although our methodology is tested using classical molecular dynamics, the ensemble generation approaches may find their greatest utility in computationally expensive simulations such asmore » first principles molecular dynamics. For such simulations, where each time step is costly, time sampling can require long simulation times because each time step must be evaluated sequentially and therefore phase space averaging is achieved through sequential operations. On the other hand, with ensemble averaging, phase space sampling can be achieved through parallel operations, since each ensemble is independent. For this reason, particularly when using massively parallel architectures, ensemble sampling can result in much shorter simulation times and exhibits similar overall computational effort.« less

Molecular Isotopic Distribution Analysis (MIDAs) with adjustable mass accuracy.

PubMed

Alves, Gelio; Ogurtsov, Aleksey Y; Yu, Yi-Kuo

2014-01-01

In this paper, we present Molecular Isotopic Distribution Analysis (MIDAs), a new software tool designed to compute molecular isotopic distributions with adjustable accuracies. MIDAs offers two algorithms, one polynomial-based and one Fourier-transform-based, both of which compute molecular isotopic distributions accurately and efficiently. The polynomial-based algorithm contains few novel aspects, whereas the Fourier-transform-based algorithm consists mainly of improvements to other existing Fourier-transform-based algorithms. We have benchmarked the performance of the two algorithms implemented in MIDAs with that of eight software packages (BRAIN, Emass, Mercury, Mercury5, NeutronCluster, Qmass, JFC, IC) using a consensus set of benchmark molecules. Under the proposed evaluation criteria, MIDAs's algorithms, JFC, and Emass compute with comparable accuracy the coarse-grained (low-resolution) isotopic distributions and are more accurate than the other software packages. For fine-grained isotopic distributions, we compared IC, MIDAs's polynomial algorithm, and MIDAs's Fourier transform algorithm. Among the three, IC and MIDAs's polynomial algorithm compute isotopic distributions that better resemble their corresponding exact fine-grained (high-resolution) isotopic distributions. MIDAs can be accessed freely through a user-friendly web-interface at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/midas/index.html.

Nonadiabatic Ab Initio Molecular Dynamics with the Floating Occupation Molecular Orbital-Complete Active Space Configuration Interaction Method [Non-Adiabatic Ab Initio Molecular Dynamics with Floating Occupation Molecular Orbitals CASCI Method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hollas, Daniel; Sistik, Lukas; Hohenstein, Edward G.

Here, we show that the floating occupation molecular orbital complete active space configuration interaction (FOMO-CASCI) method is a promising alternative to the widely used complete active space self-consistent field (CASSCF) method in direct nonadiabatic dynamics simulations. We have simulated photodynamics of three archetypal molecules in photodynamics: ethylene, methaniminium cation, and malonaldehyde. We compared the time evolution of electronic populations and reaction mechanisms as revealed by the FOMO-CASCI and CASSCF approaches. Generally, the two approaches provide similar results. Some dynamical differences are observed, but these can be traced back to energetically minor differences in the potential energy surfaces. We suggest thatmore » the FOMO-CASCI method represents, due to its efficiency and stability, a promising approach for direct ab initio dynamics in the excited state.« less

Early Experiences Porting the NAMD and VMD Molecular Simulation and Analysis Software to GPU-Accelerated OpenPOWER Platforms

PubMed Central

Stone, John E.; Hynninen, Antti-Pekka; Phillips, James C.; Schulten, Klaus

2017-01-01

All-atom molecular dynamics simulations of biomolecules provide a powerful tool for exploring the structure and dynamics of large protein complexes within realistic cellular environments. Unfortunately, such simulations are extremely demanding in terms of their computational requirements, and they present many challenges in terms of preparation, simulation methodology, and analysis and visualization of results. We describe our early experiences porting the popular molecular dynamics simulation program NAMD and the simulation preparation, analysis, and visualization tool VMD to GPU-accelerated OpenPOWER hardware platforms. We report our experiences with compiler-provided autovectorization and compare with hand-coded vector intrinsics for the POWER8 CPU. We explore the performance benefits obtained from unique POWER8 architectural features such as 8-way SMT and its value for particular molecular modeling tasks. Finally, we evaluate the performance of several GPU-accelerated molecular modeling kernels and relate them to other hardware platforms. PMID:29202130

Molecular weight kinetics and chain scission models for dextran polymers during ultrasonic degradation.

PubMed

Pu, Yuanyuan; Zou, Qingsong; Hou, Dianzhi; Zhang, Yiping; Chen, Shan

2017-01-20

Ultrasonic degradation of six dextran samples with different initial molecular weights (IMW) has been performed to investigate the degradation behavior and chain scission mechanism of dextrans. The weight-average molecular weight (Mw) and polydispersity index (D value) were monitored by High Performance Gel Permeation Chromatography (HPGPC). Results showed that Mw and D value decreased with increasing ultrasonic time, resulting in a more homologous dextran solution with lower molecular weight. A significant degradation occurred in dextrans with higher IMW, particularly at the initial stage of the ultrasonic treatment. The Malhotra model was found to well describe the molecular weight kinetics for all dextran samples. Experimental data was fitted into two chain scission models to study dextran chain scission mechanism and the model performance was compared. Results indicated that the midpoint scission model agreed well with experimental results, with a linear regression factor of R 2 >0.99. Copyright © 2016 Elsevier Ltd. All rights reserved.

Interaction of a sodium ion with the water liquid-vapor interface

NASA Technical Reports Server (NTRS)

Wilson, M. A.; Pohorille, A.; Pratt, L. R.; MacElroy, R. D. (Principal Investigator)

1989-01-01

Molecular dynamics results are presented for the density profile of a sodium ion near the water liquid-vapor interface at 320 K. These results are compared with the predictions of a simple dielectric model for the interaction of a monovalent ion with this interface. The interfacial region described by the model profile is too narrow and the profile decreases too abruptly near the solution interface. Thus, the simple model does not provide a satisfactory description of the molecular dynamics results for ion positions within two molecular diameters from the solution interface where appreciable ion concentrations are observed. These results suggest that surfaces associated with dielectric models of ionic processes at aqueous solution interfaces should be located at least two molecular diameters inside the liquid phase. A free energy expense of about 2 kcal/mol is required to move the ion within two molecular layers of the free water liquid-vapor interface.

Stability of high-mass molecular libraries: the role of the oligoporphyrin core

PubMed Central

Sezer, Uĝur; Schmid, Philipp; Felix, Lukas; Mayor, Marcel; Arndt, Markus

2015-01-01

Molecular beam techniques are a key to many experiments in physical chemistry and quantum optics. In particular, advanced matter-wave experiments with high-mass molecules profit from the availability of slow, neutral and mass-selected molecular beams that are sufficiently stable to remain intact during laser heating and photoionization mass spectrometry. We present experiments on the photostability with molecular libraries of tailored oligoporphyrins with masses up to 25 000 Da. We compare two fluoroalkylsulfanyl-functionalized libraries based on two different molecular cores that offer the same number of anchor points for functionalization but differ in their geometry and electronic properties. A pentaporphyrin core stabilizes a library of chemically well-defined molecules with more than 1600 atoms. They can be neutrally desorbed with velocities as low as 20 m/s and efficiently analyzed in photoionization mass spectrometry. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25601698

Supramolecular interactions of nonsteroidal anti-inflammatory drug in nanochannels of molecular containers: a spectroscopic, thermogravimetric and microscopic investigation.

PubMed

Maity, Banibrata; Chatterjee, Aninda; Ahmed, Sayeed Ashique; Seth, Debabrata

2014-11-10

Supramolecular host-guest complexation between the nonsteroidal anti-inflammatory drug indomethacin (IMC) and molecular containers were investigated. The weakly fluorescent drug molecule becomes highly fluorescent on complexation with different molecular containers, and time-resolved fluorescence emission spectroscopy reveals that the lifetime components of IMC significantly increase in the presence of molecular containers, compared with the lifetimes in neat water. The respective solid host-guest complexes were synthesised and characterised by Fourier transform infrared and (1) H nuclear magnetic resonance spectroscopic analysis. Microscopy techniques were used to analyse modifications of the surface morphology, owing to the formation of supramolecular complexes. The effect of the molecular container on the optical properties of IMC has also been investigated to determine the effect of nanochannels of different size and structure. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Comparative Analysis of the Molecular Adjuvants and Their Binding Efficiency with CR1.

PubMed

Saranya, B; Saxena, Shweta; Saravanan, K M; Shakila, H

2016-03-01

There are so many obstacles in developing a vaccine or vaccine technology for diseases like cancer and human immunodeficiency virus infection. While developing vaccines that target specific infection, molecular adjuvants are indispensable. These molecular adjuvants act as a vaccine delivery vehicle to the immune system to increase the effectiveness of the specific antigens. In the present work, a computational study has been done on molecular adjuvants like IgGFc, GMCSF and C3d to find out how efficiently they are binding to CR1. Sequence, structure and mutational analysis are performed on the molecular adjuvants to understand the features important for their binding with the receptor. Results obtained from our study indicate that the adjuvant IgGFc complexed with the receptor CR1 has the best binding efficiency, which can be used further to develop better vaccine technologies.

Unveiling the past of the Galactic nucleus with X-ray echoes

NASA Astrophysics Data System (ADS)

Chuard, D.; Terrier, R.; Goldwurm, A.; Clavel, M.; Soldi, S.; Morris, M. R.; Ponti, G.; Walls, M.; Chernyakova, M.

2017-12-01

Giant molecular clouds populating the central molecular zone have a high enough column density to reflect X-rays coming from strong compact sources in their neighbourhood, including possible powerful outbursts from the Galactic supermassive black hole SgrA. From observations of the molecular complex Sgr C made with the X-ray observatories XMM and Chandra between 2000 and 2014, we confirm this reflection scenario, even though the region hosts several objects (including two PWN candidates) that may be responsible for intense cosmic-ray production. By comparing data to Monte Carlo simulated reflection spectra, we are able to put the best constraints to date on the line-of-sight positions of the main bright clumps of the molecular complex. Ultimately, extending this approach by the inclusion of other molecular complexes allows us to partially reconstruct the past lightcurve of the Galactic supermassive black hole.

Fragments of the past activity of Sgr A* inferred from X-ray echoes in Sgr C

NASA Astrophysics Data System (ADS)

Chuard, D.; Terrier, R.; Goldwurm, A.; Soldi, S.; Clavel, M.; Morris, M.; Ponti, G.; Walls, M.; Chernyakova, M.

2017-10-01

Giant molecular clouds populating the central molecular zone have a high enough column density to reflect X-rays coming from strong compact sources in their neighbourhood, including possible powerful outbursts from the Galactic supermassive black hole Sgr A*. We study this reflected emission in observations of the molecular complex Sgr C made with the X-ray observatories XMM-Newton and Chandra between 2000 and 2014. We show that this complex exhibits clear variability in both space and time, which strongly favours the reflection scenario, the most likely illuminating source being Sgr A*. By comparing data to Monte-Carlo simulated reflection spectra, we are able to put the best constraints to date on the line-of-sight positions of the main bright clumps of the molecular complex. Ultimately, extending this approach by the inclusion of other molecular complexes allows us to partially reconstruct the past lightcurve of the Galactic supermassive black hole.

Squamous cell carcinoma – similarities and differences among anatomical sites

PubMed Central

Yan, Wusheng; Wistuba, Ignacio I; Emmert-Buck, Michael R; Erickson, Heidi S

2011-01-01

Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole. PMID:21938273

Study of atomic and molecular emission spectra of Sr by laser induced breakdown spectroscopy (LIBS).

PubMed

Bhatt, Chet R; Alfarraj, Bader; Ayyalasomayajula, Krishna K; Ghany, Charles; Yueh, Fang Y; Singh, Jagdish P

2015-12-01

Laser Induced Breakdown Spectroscopy (LIBS) is an ideal analytical technique for in situ analysis of elemental composition. We have performed a comparative study of the quantitative and qualitative analysis of atomic and molecular emission from LIBS spectra. In our experiments, a mixture of SrCl2 and Al2O3 in powder form was used as a sample. The atomic emission from Sr and molecular emission from SrCl and SrO observed in LIBS spectra were analyzed. The optimum laser energies, gate delays, and gate widths for selected atomic lines and molecular bands were determined from spectra recorded at various experimental parameters. These optimum experimental conditions were used to collect calibration data, and the calibration curves were used to predict the Sr concentration. Limits of detection (LODs) for selected atomic and molecular emission spectra were determined.

Inhibitory effect of hydrophilic polymer brushes on surface-induced platelet activation and adhesion.

PubMed

Zou, Yuquan; Lai, Benjamin F L; Kizhakkedathu, Jayachandran N; Brooks, Donald E

2010-12-08

Poly(N,N-dimethylacrylamide) (PDMA) brushes are successfully grown from unplasticized poly(vinyl chloride) (uPVC) by well-controlled surface-initiated atom transfer radical polymerization (SI-ATRP). Molecular weights of the grafted PDMA brushes vary from ≈ 35,000 to 2,170000 Da, while the graft density ranges from 0.08 to 1.13 chains · nm(-2). The polydispersity of the grafted PDMA brushes is controlled within 1.20 to 1.80. Platelet activation (expression of CD62) and adhesion studies reveal that the graft densities of the PDMA brushes play an important role in controlling interfacial properties. PDMA brushes with graft densities between 0.35 and 0.50 chains · nm(-2) induce a significantly reduced platelet activation compared to unmodified uPVC. Moreover, the surface adhesion of platelets on uPVC is significantly reduced by the densely grafted PDMA brushes. PDMA brushes that have high molecular weights lead to a relatively lower platelet activation compared to low-molecular-weight brushes. However, the graft density of the brush is more important than molecular weight in controlling platelet interactions with PVC. PDMA brushes do not produce any significant platelet consumption in platelet rich plasma. Up to a seven-fold decrease in the number of platelets adhered on high graft density brushes is observed compared to the bare PVC surface. Unlike the bare PVC, platelets do not form pseudopodes or change morphology on PDMA brush-coated surfaces. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The importance of the external potential on group electronegativity.

PubMed

Leyssens, Tom; Geerlings, Paul; Peeters, Daniel

2005-11-03

The electronegativity of groups placed in a molecular environment is obtained using CCSD calculations of the electron affinity and ionization energy. A point charge model is used as an approximation of the molecular environment. The electronegativity values obtained in the presence of a point charge model are compared to the isolated group property to estimate the importance of the external potential on the group's electronegativity. The validity of the "group in molecule" electronegativities is verified by comparing EEM (electronegativity equalization method) charge transfer values to the explicitly calculated natural population analysis (NPA) ones, as well as by comparing the variation in electronegativity between the isolated functional group and the functional group in the presence of a modeled environment with the variation based on a perturbation expansion of the chemical potential.

A parallel algorithm for step- and chain-growth polymerization in molecular dynamics.

PubMed

de Buyl, Pierre; Nies, Erik

2015-04-07

Classical Molecular Dynamics (MD) simulations provide insight into the properties of many soft-matter systems. In some situations, it is interesting to model the creation of chemical bonds, a process that is not part of the MD framework. In this context, we propose a parallel algorithm for step- and chain-growth polymerization that is based on a generic reaction scheme, works at a given intrinsic rate and produces continuous trajectories. We present an implementation in the ESPResSo++ simulation software and compare it with the corresponding feature in LAMMPS. For chain growth, our results are compared to the existing simulation literature. For step growth, a rate equation is proposed for the evolution of the crosslinker population that compares well to the simulations for low crosslinker functionality or for short times.

A parallel algorithm for step- and chain-growth polymerization in molecular dynamics

NASA Astrophysics Data System (ADS)

de Buyl, Pierre; Nies, Erik

2015-04-01

Classical Molecular Dynamics (MD) simulations provide insight into the properties of many soft-matter systems. In some situations, it is interesting to model the creation of chemical bonds, a process that is not part of the MD framework. In this context, we propose a parallel algorithm for step- and chain-growth polymerization that is based on a generic reaction scheme, works at a given intrinsic rate and produces continuous trajectories. We present an implementation in the ESPResSo++ simulation software and compare it with the corresponding feature in LAMMPS. For chain growth, our results are compared to the existing simulation literature. For step growth, a rate equation is proposed for the evolution of the crosslinker population that compares well to the simulations for low crosslinker functionality or for short times.

Molecular clock or erratic evolution? A tale of two genes.

PubMed Central

Ayala, F J; Barrio, E; Kwiatowski, J

1996-01-01

We have investigated the evolution of glycerol-3-phosphate dehydrogenase (Gpdh). The rate of amino acid replacements is 1 x 10(-10)/site/year when Drosophila species are compared. The rate is 2.7 times greater when Drosophila and Chymomyza species are compared; and about 5 times greater when any of those species are compared with the medfly Ceratitis capitata. This rate of 5 x 10(-10)/site/year is also the rate observed in comparisons between mammals, or between different animal phyla, or between the three multicellular kingdoms. We have also studied the evolution of Cu,Zn superoxide dismutase (Sod). The rate of amino acid replacements is about 17 x 10(-10)/site/year when comparisons are made between dipterans or between mammals, but only 5 x 10(-10) when animal phyla are compared, and only 3 x 10(-10) when the multicellular kingdoms are compared. The apparent decrease by about a factor of 5 in the rate of SOD evolution as the divergence between species increases can be consistent with the molecular clock hypothesis by assuming the covarion hypothesis (namely, that the number of amino acids that can change is constant, but the set of such amino acids changes from time to time and from lineage to lineage). However, we know of no model consistent with the molecular clock hypothesis that would account for the increase in the rate of GPDH evolution as the divergence between species increases. Images Fig. 2 Fig. 5 PMID:8876205

On a Molecular Basis, Investigate Association of Molecular Structure with Bioactive Compounds, Anti-Nutritional Factors and Chemical and Nutrient Profiles of Canola Seeds and Co-Products from Canola Processing: Comparison Crusher Plants within Canada and within China as well as between Canada and China.

PubMed

Gomaa, Walaa M S; Mosaad, Gamal M; Yu, Peiqiang

2018-04-21

The objectives of this study were to: (1) Use molecular spectroscopy as a novel technique to quantify protein molecular structures in relation to its chemical profiles and bioenergy values in oil-seeds and co-products from bio-oil processing. (2) Determine and compare: (a) protein molecular structure using Fourier transform infrared (FT/IR-ATR) molecular spectroscopy technique; (b) bioactive compounds, anti-nutritional factors, and chemical composition; and (c) bioenergy values in oil seeds (canola seeds), co-products (meal or pellets) from bio-oil processing plants in Canada in comparison with China. (3) Determine the relationship between protein molecular structural features and nutrient profiles in oil-seeds and co-products from bio-oil processing. Our results showed the possibility to characterize protein molecular structure using FT/IR molecular spectroscopy. Processing induced changes between oil seeds and co-products were found in the chemical, bioenergy profiles and protein molecular structure. However, no strong correlation was found between the chemical and nutrient profiles of oil seeds (canola seeds) and their protein molecular structure. On the other hand, co-products were strongly correlated with protein molecular structure in the chemical profile and bioenergy values. Generally, comparisons of oil seeds (canola seeds) and co-products (meal or pellets) in Canada, in China, and between Canada and China indicated the presence of variations among different crusher plants and bio-oil processing products.

Three New Teosintes (Zea spp., Poaceae) From Mexico

USDA-ARS?s Scientific Manuscript database

The discovery of new species of teosinte from México motivated the comparative study of populations from México, Guatemala and Nicaragua through detailed ecogeographic, morphologic, cytogenetic and molecular characterization. The study involved a comparative analysis of morphological, ecogeographic,...

Evaluating fossil calibrations for dating phylogenies in light of rates of molecular evolution: a comparison of three approaches.

PubMed

Lukoschek, Vimoksalehi; Scott Keogh, J; Avise, John C

2012-01-01

Evolutionary and biogeographic studies increasingly rely on calibrated molecular clocks to date key events. Although there has been significant recent progress in development of the techniques used for molecular dating, many issues remain. In particular, controversies abound over the appropriate use and placement of fossils for calibrating molecular clocks. Several methods have been proposed for evaluating candidate fossils; however, few studies have compared the results obtained by different approaches. Moreover, no previous study has incorporated the effects of nucleotide saturation from different data types in the evaluation of candidate fossils. In order to address these issues, we compared three approaches for evaluating fossil calibrations: the single-fossil cross-validation method of Near, Meylan, and Shaffer (2005. Assessing concordance of fossil calibration points in molecular clock studies: an example using turtles. Am. Nat. 165:137-146), the empirical fossil coverage method of Marshall (2008. A simple method for bracketing absolute divergence times on molecular phylogenies using multiple fossil calibration points. Am. Nat. 171:726-742), and the Bayesian multicalibration method of Sanders and Lee (2007. Evaluating molecular clock calibrations using Bayesian analyses with soft and hard bounds. Biol. Lett. 3:275-279) and explicitly incorporate the effects of data type (nuclear vs. mitochondrial DNA) for identifying the most reliable or congruent fossil calibrations. We used advanced (Caenophidian) snakes as a case study; however, our results are applicable to any taxonomic group with multiple candidate fossils, provided appropriate taxon sampling and sufficient molecular sequence data are available. We found that data type strongly influenced which fossil calibrations were identified as outliers, regardless of which method was used. Despite the use of complex partitioned models of sequence evolution and multiple calibrations throughout the tree, saturation severely compressed basal branch lengths obtained from mitochondrial DNA compared with nuclear DNA. The effects of mitochondrial saturation were not ameliorated by analyzing a combined nuclear and mitochondrial data set. Although removing the third codon positions from the mitochondrial coding regions did not ameliorate saturation effects in the single-fossil cross-validations, it did in the Bayesian multicalibration analyses. Saturation significantly influenced the fossils that were selected as most reliable for all three methods evaluated. Our findings highlight the need to critically evaluate the fossils selected by data with different rates of nucleotide substitution and how data with different evolutionary rates affect the results of each method for evaluating fossils. Our empirical evaluation demonstrates that the advantages of using multiple independent fossil calibrations significantly outweigh any disadvantages.

Length dependence of electron transport through molecular wires--a first principles perspective.

PubMed

Khoo, Khoong Hong; Chen, Yifeng; Li, Suchun; Quek, Su Ying

2015-01-07

One-dimensional wires constitute a fundamental building block in nanoscale electronics. However, truly one-dimensional metallic wires do not exist due to Peierls distortion. Molecular wires come close to being stable one-dimensional wires, but are typically semiconductors, with charge transport occurring via tunneling or thermally-activated hopping. In this review, we discuss electron transport through molecular wires, from a theoretical, quantum mechanical perspective based on first principles. We focus specifically on the off-resonant tunneling regime, applicable to shorter molecular wires (<∼4-5 nm) where quantum mechanics dictates electron transport. Here, conductance decays exponentially with the wire length, with an exponential decay constant, beta, that is independent of temperature. Different levels of first principles theory are discussed, starting with the computational workhorse - density functional theory (DFT), and moving on to many-electron GW methods as well as GW-inspired DFT + Sigma calculations. These different levels of theory are applied in two major computational frameworks - complex band structure (CBS) calculations to estimate the tunneling decay constant, beta, and Landauer-Buttiker transport calculations that consider explicitly the effects of contact geometry, and compute the transmission spectra directly. In general, for the same level of theory, the Landauer-Buttiker calculations give more quantitative values of beta than the CBS calculations. However, the CBS calculations have a long history and are particularly useful for quick estimates of beta. Comparing different levels of theory, it is clear that GW and DFT + Sigma calculations give significantly improved agreement with experiment compared to DFT, especially for the conductance values. Quantitative agreement can also be obtained for the Seebeck coefficient - another independent probe of electron transport. This excellent agreement provides confirmative evidence of off-resonant tunneling in the systems under investigation. Calculations show that the tunneling decay constant beta is a robust quantity that does not depend on details of the contact geometry, provided that the same contact geometry is used for all molecular lengths considered. However, because conductance is sensitive to contact geometry, values of beta obtained by considering conductance values where the contact geometry is changing with the molecular junction length can be quite different. Experimentally measured values of beta in general compare well with beta obtained using DFT + Sigma and GW transport calculations, while discrepancies can be attributed to changes in the experimental contact geometries with molecular length. This review also summarizes experimental and theoretical efforts towards finding perfect molecular wires with high conductance and small beta values.

Modulation of circular current and associated magnetic field in a molecular junction: A new approach

NASA Astrophysics Data System (ADS)

Patra, Moumita; Maiti, Santanu K.

2017-03-01

A new proposal is given to control local magnetic field in a molecular junction. In presence of finite bias a net circular current is established in the molecular ring which induces a magnetic field at its centre. Allowing a direct coupling between two electrodes, due to their close proximity, and changing its strength we can regulate circular current as well as magnetic field for a wide range, without disturbing any other physical parameters. We strongly believe that our proposal is quite robust compared to existing approaches of controlling local magnetic field and can be verified experimentally.

The any particle molecular orbital grid-based Hartree-Fock (APMO-GBHF) approach

NASA Astrophysics Data System (ADS)

Posada, Edwin; Moncada, Félix; Reyes, Andrés

2018-02-01

The any particle molecular orbital grid-based Hartree-Fock approach (APMO-GBHF) is proposed as an initial step to perform multi-component post-Hartree-Fock, explicitly correlated, and density functional theory methods without basis set errors. The method has been applied to a number of electronic and multi-species molecular systems. Results of these calculations show that the APMO-GBHF total energies are comparable with those obtained at the APMO-HF complete basis set limit. In addition, results reveal a considerable improvement in the description of the nuclear cusps of electronic and non-electronic densities.

The importance of the biomimetic composites components for recreating the optical properties and molecular composition of intact dental tissues.

NASA Astrophysics Data System (ADS)

Seredin, P. V.; Goloshchapov, D. L.; Gushchin, M. S.; Ippolitov, Y. A.; Prutskij, T.

2017-11-01

The objective of this paper was to investigate whether it is possible to obtain biomimetic materials recreating the luminescent properties and molecular composition of intact dental tissues. Biomimetic materials were produced and their properties compared with native dental tissues. In addition, the overall contribution of the organic and non-organic components in the photoluminescence band was investigated. The results showed that it is possible to develop biomimetic materials with similar molecular composition and optical properties to native dental tissues for the early identification of dental caries.

Dielectric relaxation of ethylene carbonate and propylene carbonate from molecular dynamics simulations

DOE PAGES

Chaudhari, Mangesh I.; You, Xinli; Pratt, Lawrence R.; ...

2015-11-24

Ethylene carbonate (EC) and propylene carbonate (PC) are widely used solvents in lithium (Li)-ion batteries and supercapacitors. Ion dissolution and diffusion in those media are correlated with solvent dielectric responses. Here, we use all-atom molecular dynamics simulations of the pure solvents to calculate dielectric constants and relaxation times, and molecular mobilities. The computed results are compared with limited available experiments to assist more exhaustive studies of these important characteristics. As a result, the observed agreement is encouraging and provides guidance for further validation of force-field simulation models for EC and PC solvents.

Nd:YAG-CO(2) double-pulse laser induced breakdown spectroscopy of organic films.

PubMed

Weidman, Matthew; Baudelet, Matthieu; Palanco, Santiago; Sigman, Michael; Dagdigian, Paul J; Richardson, Martin

2010-01-04

Laser-induced breakdown spectroscopy (LIBS) using double-pulse irradiation with Nd:YAG and CO(2) lasers was applied to the analysis of a polystyrene film on a silicon substrate. An enhanced emission signal, compared to single-pulse LIBS using a Nd:YAG laser, was observed from atomic carbon, as well as enhanced molecular emission from C(2) and CN. This double-pulse technique was further applied to 2,4,6-trinitrotoluene residues, and enhanced LIBS signals for both atomic carbon and molecular CN emission were observed; however, no molecular C(2) emission was detected.

Properties of cellulase as template molecule on chitosan—methyl methacrylate membrane

NASA Astrophysics Data System (ADS)

Lian, Qi; Zheng, Xuefang; Wu, Haixia; Song, Shitao; Wang, Dongjun

2015-12-01

In this study, a novel molecular imprinting membrane made of chitosan and methyl methacrylate (MMA) was fabricated with cellulase as template molecule and the thermal response to cellulase was characterized. The film was characterized by infrared spectroscopy (IR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and the permeation experiment. The results showed that the space structure of the film was as similar as the cellulase. Moreover, the membrane had advanced molecular imprinting capability to cellulase comparing to pepsin and pectinase at any temperature and the film had excellent ability to identify specific template molecule (cellulase) at the synthesis temperature compared to other temperatures.

Mechanisms of Aging of Phosphylated Serine Hydrolases

DTIC Science & Technology

2009-08-25

These findings can be compared to previous molecular dynamics research on AChE undertaken by Hurley et al. (2005) that reported a net- RMSD of...1.2 Å associated with in silico inhibition (but not aging) of AChE by the nerve agent VX. This RMSD is comparable to our result of 1.4 Å for simulated ...4 4.2. Mass spectrometry…………………………………………………………………. 5 4.3. Computational molecular modeling……………………………………………….. 7 5

Diffusion blotting: a rapid and simple method for production of multiple blots from a single gel.

PubMed

Olsen, Ingrid; Wiker, Harald G

2015-01-01

A very simple and fast method for diffusion blotting of proteins from precast SDS-PAGE gels on a solid plastic support was developed. Diffusion blotting for 3 min gives a quantitative transfer of 10 % compared to 1-h electroblotting. For each subsequent blot from the same gel a doubling of transfer time is necessary to obtain the same amount of protein onto each blot. High- and low-molecular-weight components are transferred equally efficiently when compared to electroblotting. However, both methods do give a higher total transfer of the low-molecular-weight proteins compared to the large proteins. The greatest advantage of diffusion blotting is that several blots can be made from each lane, thus enabling testing of multiple antisera on virtually identical blots. The gel remains on the plastic support, which prevents it from stretching or shrinking. This ensures identical blots and facilitates more reliable molecular weight determination. Furthermore the proteins remaining in the gel can be stained with Coomassie Brilliant Blue or other methods for exact and easy comparison with the developed blots. These advantages make diffusion blotting the method of choice when quantitative protein transfer is not required.

Ecology has contrasting effects on genetic variation within species versus rates of molecular evolution across species in water beetles.

PubMed

Fujisawa, Tomochika; Vogler, Alfried P; Barraclough, Timothy G

2015-01-22

Comparative analysis is a potentially powerful approach to study the effects of ecological traits on genetic variation and rate of evolution across species. However, the lack of suitable datasets means that comparative studies of correlates of genetic traits across an entire clade have been rare. Here, we use a large DNA-barcode dataset (5062 sequences) of water beetles to test the effects of species ecology and geographical distribution on genetic variation within species and rates of molecular evolution across species. We investigated species traits predicted to influence their genetic characteristics, such as surrogate measures of species population size, latitudinal distribution and habitat types, taking phylogeny into account. Genetic variation of cytochrome oxidase I in water beetles was positively correlated with occupancy (numbers of sites of species presence) and negatively with latitude, whereas substitution rates across species depended mainly on habitat types, and running water specialists had the highest rate. These results are consistent with theoretical predictions from nearly-neutral theories of evolution, and suggest that the comparative analysis using large databases can give insights into correlates of genetic variation and molecular evolution.

Cellular and molecular investigations of the adhesion and mechanics of Listeria monocytogenes

NASA Astrophysics Data System (ADS)

Eskhan, Asma Omar

Atomic force microscopy has been used to quantify the adherence and mechanical properties of an array of L. monocytogenes strains and their surface biopolymers. First, eight L. monocytogenes strains that represented the two major lineages of the species were compared for their adherence and mechanics at cellular and molecular levels. Our results indicated that strains of lineage' II were characterized by higher adhesion and Young's moduli, longer and more rigid surface biopolymers and lower specific and nonspecific forces when compared to lineage' I strains. Additionally, adherence and mechanical properties of eight L. monocytogenes epidemic and environmental strains were probed. Our results pointed to that environmental and epidemic strains representative of a given lineage were similar in their adherence and mechanical properties when investigated at a cellular level. However, when the molecular properties of the strains were considered, epidemic strains were characterized by higher specific and nonspecific forces, shorter, denser and more flexible biopolymers compared to environmental strains. Second, the role of environmental pH conditions of growth on the adhesion and mechanics of a pathogenic L. monocytogenes EGDe was investigated. Our results pointed to a transition in the adhesion energies for cells cultured at pH 7. In addition, when the types of molecular forces that govern the adhesion were quantified using Poisson statistical approach and using a new proposed method, specific hydrogen-bond energies dominated the bacterial adhesion process. Such a finding is instrumental to researchers designing methods to control bacterial adhesion. Similarly, bacterial cells underwent a transition in their mechanical properties. We have shown that cells cultured at pH 7 were the most rigid compared to those cultured in lower or higher pH conditions of growth. Due to transitions observed in adherence and mechanics when cells were cultured at pH 7, we hypothesized that adhesion and mechanics are correlated. To test this hypothesis, nonadhesive and adhesive models of contact mechanics were used to estimate Young's moduli. Our results indicated that the nonadhesive model of contact mechanics estimated 18 % more rigid bacterial cells. Our results thus point to the importance of considering molecular details when investigating bacterial adhesion and mechanics.

Comprehensive and quantitative profiling of lipid species in human milk, cow milk and a phospholipid-enriched milk formula by GC and MS/MSALL.

PubMed

Sokol, Elena; Ulven, Trond; Færgeman, Nils J; Ejsing, Christer S

2015-06-01

Here we present a workflow for in-depth analysis of milk lipids that combines gas chromatography (GC) for fatty acid (FA) profiling and a shotgun lipidomics routine termed MS/MS ALL for structural characterization of molecular lipid species. To evaluate the performance of the workflow we performed a comparative lipid analysis of human milk, cow milk, and Lacprodan® PL-20, a phospholipid-enriched milk protein concentrate for infant formula. The GC analysis showed that human milk and Lacprodan have a similar FA profile with higher levels of unsaturated FAs as compared to cow milk. In-depth lipidomic analysis by MS/MS ALL revealed that each type of milk sample comprised distinct composition of molecular lipid species. Lipid class composition showed that the human and cow milk contain a higher proportion of triacylglycerols (TAGs) as compared to Lacprodan. Notably, the MS/MS ALL analysis demonstrated that the similar FA profile of human milk and Lacprodan determined by GC analysis is attributed to the composition of individual TAG species in human milk and glycerophospholipid species in Lacprodan. Moreover, the analysis of TAG molecules in Lacprodan and cow milk showed a high proportion of short-chain FAs that could not be monitored by GC analysis. The results presented here show that complementary GC and MS/MS ALL analysis is a powerful approach for characterization of molecular lipid species in milk and milk products. : Milk lipid analysis is routinely performed using gas chromatography. This method reports the total fatty acid composition of all milk lipids, but provides no structural or quantitative information about individual lipid molecules in milk or milk products. Here we present a workflow that integrates gas chromatography for fatty acid profiling and a shotgun lipidomics routine termed MS/MS ALL for structural analysis and quantification of molecular lipid species. We demonstrate the efficacy of this complementary workflow by a comparative analysis of molecular lipid species in human milk, cow milk, and a milk-based supplement used for infant formula.

Comprehensive and quantitative profiling of lipid species in human milk, cow milk and a phospholipid-enriched milk formula by GC and MS/MSALL

PubMed Central

Sokol, Elena; Ulven, Trond; Færgeman, Nils J; Ejsing, Christer S

2015-01-01

Here we present a workflow for in-depth analysis of milk lipids that combines gas chromatography (GC) for fatty acid (FA) profiling and a shotgun lipidomics routine termed MS/MSALL for structural characterization of molecular lipid species. To evaluate the performance of the workflow we performed a comparative lipid analysis of human milk, cow milk, and Lacprodan® PL-20, a phospholipid-enriched milk protein concentrate for infant formula. The GC analysis showed that human milk and Lacprodan have a similar FA profile with higher levels of unsaturated FAs as compared to cow milk. In-depth lipidomic analysis by MS/MSALL revealed that each type of milk sample comprised distinct composition of molecular lipid species. Lipid class composition showed that the human and cow milk contain a higher proportion of triacylglycerols (TAGs) as compared to Lacprodan. Notably, the MS/MSALL analysis demonstrated that the similar FA profile of human milk and Lacprodan determined by GC analysis is attributed to the composition of individual TAG species in human milk and glycerophospholipid species in Lacprodan. Moreover, the analysis of TAG molecules in Lacprodan and cow milk showed a high proportion of short-chain FAs that could not be monitored by GC analysis. The results presented here show that complementary GC and MS/MSALL analysis is a powerful approach for characterization of molecular lipid species in milk and milk products. Practical applications : Milk lipid analysis is routinely performed using gas chromatography. This method reports the total fatty acid composition of all milk lipids, but provides no structural or quantitative information about individual lipid molecules in milk or milk products. Here we present a workflow that integrates gas chromatography for fatty acid profiling and a shotgun lipidomics routine termed MS/MSALL for structural analysis and quantification of molecular lipid species. We demonstrate the efficacy of this complementary workflow by a comparative analysis of molecular lipid species in human milk, cow milk, and a milk-based supplement used for infant formula. PMID:26089741

Effect of molecular weight profile of sorghum proanthocyanidins on resistant starch formation.

PubMed

Barros, Frederico; Awika, Joseph; Rooney, Lloyd W

2014-04-01

There is a growing interest to increase resistant starch (RS) in foods through natural modification of starch. Sorghum tannins (proanthocyanidins, PAs) were recently reported to interact with starch, increasing RS. However, there is no information about how the molecular weight profile of PAs affects RS formation. This study investigated how different-molecular-weight PAs from sorghum affected RS formation in different starch models. The levels of RS were higher (331-437 mg g(-1)) when high-amylose starch was cooked with phenolic extracts containing mostly high-molecular-weight PAs compared with extracts containing lower-molecular-weight PAs or monomeric catechin (249-285 mg g(-1)). In general, binding capacity of PAs with amylose increased proportionally with molecular weight. For example, the percentage of PAs bound to amylose increased from 45% (PAs with degree of polymerization (DP) = 6) to 94% (polymeric PAs, DP > 10). The results demonstrate that molecular weight of the PAs directly affects their interaction with starch: the higher the molecular weight, the stronger the binding to amylose and the higher the RS formation. Polymeric PAs from sorghum can naturally modify starch by interacting strongly with amylose and are thus most suitable to produce foods with higher RS. © 2013 Society of Chemical Industry.

Molecular Imprinting of Macromolecules for Sensor Applications

PubMed Central

Saylan, Yeşeren; Yilmaz, Fatma; Özgür, Erdoğan; Derazshamshir, Ali; Yavuz, Handan; Denizli, Adil

2017-01-01

Molecular recognition has an important role in numerous living systems. One of the most important molecular recognition methods is molecular imprinting, which allows host compounds to recognize and detect several molecules rapidly, sensitively and selectively. Compared to natural systems, molecular imprinting methods have some important features such as low cost, robustness, high recognition ability and long term durability which allows molecularly imprinted polymers to be used in various biotechnological applications, such as chromatography, drug delivery, nanotechnology, and sensor technology. Sensors are important tools because of their ability to figure out a potentially large number of analytical difficulties in various areas with different macromolecular targets. Proteins, enzymes, nucleic acids, antibodies, viruses and cells are defined as macromolecules that have wide range of functions are very important. Thus, macromolecules detection has gained great attention in concerning the improvement in most of the studies. The applications of macromolecule imprinted sensors will have a spacious exploration according to the low cost, high specificity and stability. In this review, macromolecules for molecularly imprinted sensor applications are structured according to the definition of molecular imprinting methods, developments in macromolecular imprinting methods, macromolecular imprinted sensors, and conclusions and future perspectives. This chapter follows the latter strategies and focuses on the applications of macromolecular imprinted sensors. This allows discussion on how sensor strategy is brought to solve the macromolecules imprinting. PMID:28422082

Molecular Imprinting of Macromolecules for Sensor Applications.

PubMed

Saylan, Yeşeren; Yilmaz, Fatma; Özgür, Erdoğan; Derazshamshir, Ali; Yavuz, Handan; Denizli, Adil

2017-04-19

Molecular recognition has an important role in numerous living systems. One of the most important molecular recognition methods is molecular imprinting, which allows host compounds to recognize and detect several molecules rapidly, sensitively and selectively. Compared to natural systems, molecular imprinting methods have some important features such as low cost, robustness, high recognition ability and long term durability which allows molecularly imprinted polymers to be used in various biotechnological applications, such as chromatography, drug delivery, nanotechnology, and sensor technology. Sensors are important tools because of their ability to figure out a potentially large number of analytical difficulties in various areas with different macromolecular targets. Proteins, enzymes, nucleic acids, antibodies, viruses and cells are defined as macromolecules that have wide range of functions are very important. Thus, macromolecules detection has gained great attention in concerning the improvement in most of the studies. The applications of macromolecule imprinted sensors will have a spacious exploration according to the low cost, high specificity and stability. In this review, macromolecules for molecularly imprinted sensor applications are structured according to the definition of molecular imprinting methods, developments in macromolecular imprinting methods, macromolecular imprinted sensors, and conclusions and future perspectives. This chapter follows the latter strategies and focuses on the applications of macromolecular imprinted sensors. This allows discussion on how sensor strategy is brought to solve the macromolecules imprinting.

High Pressure Size Exclusion Chromatography (HPSEC) Determination of Dissolved Organic Matter Molecular Weight Revisited: Accounting for Changes in Stationary Phases, Analytical Standards, and Isolation Methods.

PubMed

McAdams, Brandon C; Aiken, George R; McKnight, Diane M; Arnold, William A; Chin, Yu-Ping

2018-01-16

We reassessed the molecular weight of dissolved organic matter (DOM) determined by high pressure size exclusion chromatography (HPSEC) using measurements made with different columns and various generations of polystyrenesulfonate (PSS) molecular weight standards. Molecular weight measurements made with a newer generation HPSEC column and PSS standards from more recent lots are roughly 200 to 400 Da lower than initial measurements made in the early 1990s. These updated numbers match DOM molecular weights measured by colligative methods and fall within a range of values calculated from hydroxyl radical kinetics. These changes suggest improved accuracy of HPSEC molecular weight measurements that we attribute to improved accuracy of PSS standards and changes in the column packing. We also isolated DOM from wetlands in the Prairie Pothole Region (PPR) using XAD-8, a cation exchange resin, and PPL, a styrene-divinylbenzene media, and observed little difference in molecular weight and specific UV absorbance at 280 nm (SUVA 280 ) between the two solid phase extraction resins, suggesting they capture similar DOM moieties. PPR DOM also showed lower SUVA 280 at similar weights compared to DOM isolates from a global range of environments, which we attribute to oxidized sulfur in PPR DOM that would increase molecular weight without affecting SUVA 280 .

Molecular and morphological characterization of Xiphinema chambersi population from live oak in Jekyll Island, Georgia, with comments on morphometric variations

Treesearch

Zafar A. Handoo; Lynn K. Carta; Andrea M. Skantar; Sergei A. Subbotin; Stephen Fraedrich

2016-01-01

A population of Xiphinema chambersi from the root zone around live oak (Quercus virginiana Mill.) trees on Jekyll Island, GA, is described using both morphological and molecular tools and compared with descriptions of type specimens. Initially, because of a few morphological differences, this nematode was thought to represent an undescribed species. However, on further...