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Sample records for 3d qsar study

  1. Receptor-based 3D-QSAR in Drug Design: Methods and Applications in Kinase Studies.

    PubMed

    Fang, Cheng; Xiao, Zhiyan

    2016-01-01

    Receptor-based 3D-QSAR strategy represents a superior integration of structure-based drug design (SBDD) and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis. It combines the accurate prediction of ligand poses by the SBDD approach with the good predictability and interpretability of statistical models derived from the 3D-QSAR approach. Extensive efforts have been devoted to the development of receptor-based 3D-QSAR methods and two alternative approaches have been exploited. One associates with computing the binding interactions between a receptor and a ligand to generate structure-based descriptors for QSAR analyses. The other concerns the application of various docking protocols to generate optimal ligand poses so as to provide reliable molecular alignments for the conventional 3D-QSAR operations. This review highlights new concepts and methodologies recently developed in the field of receptorbased 3D-QSAR, and in particular, covers its application in kinase studies.

  2. 3-D QSAR studies on histone deacetylase inhibitors. A GOLPE/GRID approach on different series of compounds.

    PubMed

    Ragno, Rino; Simeoni, Silvia; Valente, Sergio; Massa, Silvio; Mai, Antonello

    2006-01-01

    Docking simulation and three-dimensional quantitative structure-activity relationships (3D-QSARs) analyses were conducted on four series of HDAC inhibitors. The studies were performed using the GRID/GOLPE combination using structure-based alignment. Twelve 3-D QSAR models were derived and discussed. Compared to previous studies on similar inhibitors, the present 3-D QSAR investigation proved to be of higher statistical value, displaying for the best global model r2, q2, and cross-validated SDEP values of 0.94, 0.83, and 0.41, respectively. A comparison of the 3-D QSAR maps with the structural features of the binding site showed good correlation. The results of 3D-QSAR and docking studies validated each other and provided insight into the structural requirements for anti-HDAC activity. To our knowledge this is the first 3-D QSAR application on a broad molecular diversity training set of HDACIs.

  3. Synthesis, in vitro antitubercular activity and 3D-QSAR study of 1,4-dihydropyridines.

    PubMed

    Manvar, Atul T; Pissurlenkar, Raghuvir R S; Virsodia, Vijay R; Upadhyay, Kuldip D; Manvar, Dinesh R; Mishra, Arun K; Acharya, Hrishikesh D; Parecha, Alpesh R; Dholakia, Chintan D; Shah, Anamik K; Coutinho, Evans C

    2010-05-01

    In continuation of our research program on new antitubercular agents, this article is a report of the synthesis of 97 various symmetrical, unsymmetrical, and N-substituted 1,4-dihydropyridines. The synthesized molecules were tested for their activity against M. tuberculosis H (37)Rv strain with rifampin as the standard drug. The percentage inhibition was found in the range 3-93%. In an effort to understand the relationship between structure and activity, 3D-QSAR studies were also carried out on a subset that is representative of the molecules synthesized. For the generation of the QSAR models, a training set of 35 diverse molecules representing the synthesized molecules was utilized. The molecules were aligned using the atom-fit technique. The CoMFA and CoMSIA models generated on the molecules aligned by the atom-fit method show a correlation coefficient (r (2)) of 0.98 and 0.95 with cross-validated r (2)(q (2)) of 0.56 and 0.62, respectively. The 3D-QSAR models were externally validated against a test set of 19 molecules (aligned previously with the training set) for which the predictive r(2)(r(r)(pred)) is recorded as 0.74 and 0.69 for the CoMFA and CoMSIA models, respectively. The models were checked for chance correlation through y-scrambling. The QSAR models revealed the importance of the conformational flexibility of the substituents in antitubercular activity.

  4. Design, synthesis and 3D-QSAR study of cytotoxic flavonoid derivatives.

    PubMed

    Ou, Lili; Han, Shuang; Ding, Wenbo; Chen, Zhe; Ye, Ziqi; Yang, Hongyu; Zhang, Goulin; Lou, Yijia; Chen, Jian-Zhong; Yu, Yongping

    2011-08-01

    Three series of flavonoid derivatives were designed and synthesized. All synthesized compounds were evaluated for cytotoxic activities against five human cancer cell lines, including K562, PC-3, MCF-7, A549, and HO8910. Among the compounds tested, compound 9 d exhibited the most potent cytotoxic activity with IC(50) values of 2.76-6.98 μM. Further comparative molecular field analysis was performed to conduct a 3D quantitative structure-activity relationship study. The generated 3D-QSAR model could be used for further rational design of novel flavonoid analogs as highly potent cytotoxic agents.

  5. 3-D QSARS FOR RANKING AND PRIORITIZATION OF LARGE CHEMICAL DATASETS: AN EDC CASE STUDY

    EPA Science Inventory

    The COmmon REactivity Pattern (COREPA) approach is a three-dimensional structure activity (3-D QSAR) technique that permits identification and quantification of specific global and local steroelectronic characteristics associated with a chemical's biological activity. It goes bey...

  6. 3D-QSAR and molecular docking studies on HIV protease inhibitors

    NASA Astrophysics Data System (ADS)

    Tong, Jianbo; Wu, Yingji; Bai, Min; Zhan, Pei

    2017-02-01

    In order to well understand the chemical-biological interactions governing their activities toward HIV protease activity, QSAR models of 34 cyclic-urea derivatives with inhibitory HIV were developed. The quantitative structure activity relationship (QSAR) model was built by using comparative molecular similarity indices analysis (CoMSIA) technique. And the best CoMSIA model has rcv2, rncv2 values of 0.586 and 0.931 for cross-validated and non-cross-validated. The predictive ability of CoMSIA model was further validated by a test set of 7 compounds, giving rpred2 value of 0.973. Docking studies were used to find the actual conformations of chemicals in active site of HIV protease, as well as the binding mode pattern to the binding site in protease enzyme. The information provided by 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 34 cyclic-urea derivatives and help to design potential anti-HIV protease molecules.

  7. Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters.

    PubMed

    Radadiya, Ashish; Khedkar, Vijay; Bavishi, Abhay; Vala, Hardevsinh; Thakrar, Shailesh; Bhavsar, Dhairya; Shah, Anamik; Coutinho, Evans

    2014-03-03

    A series of symmetrical and unsymmetrical 1,4-dihydropyridines were synthesized by a rapid, single pot microwave irradiation (MWI) based protocol along with conventional approach and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their tumor cell cytotoxicity in HL-60 tumor cells. A 3D-QSAR study using CoMFA and CoMSIA was carried out to decipher the factors governing MDR reversing ability in cancer. The resulting contour maps derived by the best 3D-QSAR models provide a good insight into the molecular features relevant to the biological activity in this series of analogs. 3D contour maps as a result of 3D-QSAR were utilized to identify some novel features that can be incorporated into the 1,4-dihydropyridine framework to enhance the activity.

  8. Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

    NASA Astrophysics Data System (ADS)

    Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

    2013-08-01

    The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

  9. 3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor.

    PubMed

    Geldenhuys, Werner J; Novotny, Nicholas; Malan, Sarel F; Van der Schyf, Cornelis J

    2013-03-15

    Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure-activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (σ1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q(2)) regression value of 0.6, and a non-cross validated r(2) of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of a test set with an r(2) >0.7. We also describe here the docking of the PCU-derived compounds into a homology model of the sigma-1 (σ1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [(3)H]pentazocine binding assay an oxa-PCU, NGP1-01 (IC50=1.78μM) and its phenethyl derivative (IC50=1.54μM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(σ1) receptor.

  10. Pharmacophore modeling, 3D-QSAR and docking study of 2-phenylpyrimidine analogues as selective PDE4B inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-04-07

    Pharmacophore modeling, molecular docking, and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 2-phenylpyrimidine series as PDE4B selective inhibitors. A five point pharmacophore model was developed using 87 molecules having pIC50 ranging from 8.52 to 5.07. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2)=0.918), cross validation coefficient (Q(2)=0.852), and F value (175) at 4 component PLS factor. The external validation indicated that our QSAR model possessed high predictive power (R(2)=0.70). The generated model was further validated by enrichment studies using the decoy test. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviation. A 10ns molecular dynamics simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Further, similar orientation was observed between the superposition of the conformations of 85 after MD simulation and best XP-docking pose; MD simulation and 3D-QSAR pose; best XP-docking and 3D-QSAR poses. Outcomes of the present study provide insight in designing novel molecules with better PDE4B selective inhibitory activity.

  11. 3D QSAR studies, pharmacophore modeling and virtual screening on a series of steroidal aromatase inhibitors.

    PubMed

    Xie, Huiding; Qiu, Kaixiong; Xie, Xiaoguang

    2014-11-14

    Aromatase inhibitors are the most important targets in treatment of estrogen-dependent cancers. In order to search for potent steroidal aromatase inhibitors (SAIs) with lower side effects and overcome cellular resistance, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of SAIs to build 3D QSAR models. The reliable and predictive CoMFA and CoMSIA models were obtained with statistical results (CoMFA: q² = 0.636, r²(ncv) = 0.988, r²(pred) = 0.658; CoMSIA: q² = 0.843, r²(ncv) = 0.989, r²(pred) = 0.601). This 3D QSAR approach provides significant insights that can be used to develop novel and potent SAIs. In addition, Genetic algorithm with linear assignment of hypermolecular alignment of database (GALAHAD) was used to derive 3D pharmacophore models. The selected pharmacophore model contains two acceptor atoms and four hydrophobic centers, which was used as a 3D query for virtual screening against NCI2000 database. Six hit compounds were obtained and their biological activities were further predicted by the CoMFA and CoMSIA models, which are expected to design potent and novel SAIs.

  12. 3D-QSAR studies on chromone derivatives as HIV-1 protease inhibitors

    NASA Astrophysics Data System (ADS)

    Ungwitayatorn, Jiraporn; Samee, Weerasak; Pimthon, Jutarat

    2004-02-01

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was applied to a series of 30 chromone derivatives, a new class of HIV-1 protease inhibitors. The best predictive CoMFA model gives cross-validated r2 ( q2)=0.763, non-cross-validated r2=0.967, standard error of estimate ( S)=5.092, F=90.701. The best CoMSIA model has q2=0.707, non-cross-validated r2=0.943, S=7.018, F=51.734, included steric, electrostatic, hydrophobic, and hydrogen bond donor fields. The predictive ability of these models was validated by a set of five compounds that were not included in the training set. The calculated (predicted) and experimental inhibitory activities were well correlated. The contour maps obtained from CoMFA and CoMSIA models were in agreement with the previous docking study for this chromone series.

  13. 3D-QSAR study of hallucinogenic phenylalkylamines by using CoMFA approach

    NASA Astrophysics Data System (ADS)

    Zhang, Zhuoyong; An, Liying; Hu, Wenxiang; Xiang, Yuhong

    2007-04-01

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) has been studied on 90 hallucinogenic phenylalkylamines by the comparative molecular field analysis (CoMFA). Two conformations were compared during the modeling. Conformation I referred to the amino group close to ring position 6 and conformation II related to the amino group trans to the phenyl ring. Satisfactory results were obtained by using both conformations. There were still differences between the two models. The model based on conformation I got better statistical results than the one about conformation II. And this may suggest that conformation I be preponderant when the hallucinogenic phenylalkylamines interact with the receptor. To further confirm the predictive capability of the CoMFA model, 18 compounds with conformation I were randomly selected as a test set and the remaining ones as training set. The best CoMFA model based on the training set had a cross-validation coefficient q 2 of 0.549 at five components and non cross-validation coefficient R 2 of 0.835, the standard error of estimation was 0.219. The model showed good predictive ability in the external test with a coefficient R pre 2 of 0.611. The CoMFA coefficient contour maps suggested that both steric and electrostatic interactions play an important role. The contributions from the steric and electrostatic fields were 0.450 and 0.550, respectively.

  14. Docking and 3-D QSAR studies on the binding of tetrahydropyrimid-2-one HIV-1 protease inhibitors

    NASA Astrophysics Data System (ADS)

    Rao, Shashidhar N.; Balaji, Govardhan A.; Balaji, Vitukudi N.

    2013-06-01

    We present molecular docking and 3-D QSAR studies on a series of tetrahydropyrimid-2-one HIV-1 protease inhibitors whose binding affinities to the enzyme span nearly 6 orders of magnitude. The docking investigations have been carried out with Surflex (GEOM, GEOMX) and Glide (SP and XP) methodologies available through Tripos and Schrodinger suite of tools in the context of Sybyl-X and Maestro interfaces, respectively. The alignments for 3-D QSAR studies were obtained by using the automated Surflex-SIM methodology in Sybyl-X and the analyses were performed using the CoMFA and CoMSIA methods. Additionally, the top-ranked poses obtained from various docking protocols were also employed to generate CoMFA and CoMSIA models to evaluate the qualitative consistency of the docked models with experimental data. Our studies demonstrate that while there are a number of common features in the docked models obtained from Surflex-dock and Glide methodologies, the former sets of models are generally better correlated with deduced experimental binding modes based on the X-ray structures of known HIV-1 protease complexes with cyclic ureas. The urea moiety common to all the ligands are much more tightly aligned in Surflex docked structures than in the models obtained from Glide SP and XP dockings. The 3-D QSAR models are qualitatively and quantitatively similar to those previously reported, suggesting the utility of automatically generated alignments from Surflex-SIM methodology.

  15. 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

  16. Docking, 3D-QSAR studies and in silico ADME prediction on c-Src tyrosine kinase inhibitors.

    PubMed

    Tintori, Cristina; Magnani, Matteo; Schenone, Silvia; Botta, Maurizio

    2009-03-01

    Docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) analysis were performed on a wide set of c-Src inhibitors. The study was conducted using a structure-based alignment and by applying the GRID/GOLPE approach. The present 3D-QSAR investigation proved to be of good statistical value, displaying r(2), q(2) and cross-validation SDEP values of 0.94, 0.84 and 0.42, respectively. Moreover, such a model also proved to be capable of predicting the activities of an external test set of compounds. The availability of the 3D structure of the target made possible the interpretation of steric and electrostatic maps within the binding site environment and provided useful insight into the structural requirements for inhibitory activity against c-Src. Two regions whose occupation by hydrophobic portions of ligands would favourably affect the activity were clearly identified. Moreover, hydrogen bond interactions involving residues Met343, Asp406 and Ser347 emerged as playing a key role in determining the affinity of the active inhibitors toward c-Src. Furthermore, the inhibitors bearing a basic nitrogen provided enhanced potency through protonation and salt bridge formation with Asp350. A preliminary pharmacokinetic profile of the molecules under analysis was also drawn on the basis of Volsurf predictions.

  17. Molecular docking and 3D-QSAR studies on gag peptide analogue inhibitors interacting with human cyclophilin A.

    PubMed

    Cui, Meng; Huang, Xiaoqin; Luo, Xiaomin; Briggs, James M; Ji, Ruyun; Chen, Kaixian; Shen, Jianhua; Jiang, Hualiang

    2002-11-21

    The interaction of a series gag peptide analogues with human cyclophilin A (hCypA) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) and divide-and-conquer methods were applied to locate the binding orientations and conformations of the inhibitors interacting with hCypA. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. A novel interaction model was identified for inhibitors 11, 15, and 17 whose N-termini were modified by addition of the deaminovaline (Dav) group and the C-termini of 15 and 17 were modified by addition of a benzyl group. Accordingly, two new binding sites (sites A and D in Figure 1) were revealed, which show a strong correlation with inhibitor potency and thus can be used as a starting point for new inhibitor design. In addition, two predictive 3D-QSAR models were obtained by CoMFA and CoMSIA analyses based on the binding conformations derived from the molecular docking calculations. The reasonable r(cross)(2) (cross-validated) values 0.738 and 0.762 were obtained for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four peptide analogues test set. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding groove of hCypA. This indicates the reasonableness of the binding model of the inhibitors with hCypA. Considering all these results together with the valuable clues of binding from references published recently, reasonable pharmacophore elements have been suggested, demonstrating that the 3D-QSAR models about peptide analogue inhibitors are expected to be further employed in predicting activities of the novel compounds for inhibiting hCypA.

  18. Advantages and limitations of classic and 3D QSAR approaches in nano-QSAR studies based on biological activity of fullerene derivatives

    NASA Astrophysics Data System (ADS)

    Jagiello, Karolina; Grzonkowska, Monika; Swirog, Marta; Ahmed, Lucky; Rasulev, Bakhtiyor; Avramopoulos, Aggelos; Papadopoulos, Manthos G.; Leszczynski, Jerzy; Puzyn, Tomasz

    2016-09-01

    In this contribution, the advantages and limitations of two computational techniques that can be used for the investigation of nanoparticles activity and toxicity: classic nano-QSAR (Quantitative Structure-Activity Relationships employed for nanomaterials) and 3D nano-QSAR (three-dimensional Quantitative Structure-Activity Relationships, such us Comparative Molecular Field Analysis, CoMFA/Comparative Molecular Similarity Indices Analysis, CoMSIA analysis employed for nanomaterials) have been briefly summarized. Both approaches were compared according to the selected criteria, including: efficiency, type of experimental data, class of nanomaterials, time required for calculations and computational cost, difficulties in the interpretation. Taking into account the advantages and limitations of each method, we provide the recommendations for nano-QSAR modellers and QSAR model users to be able to determine a proper and efficient methodology to investigate biological activity of nanoparticles in order to describe the underlying interactions in the most reliable and useful manner.

  19. A structure-activity relationship study of catechol- O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods

    NASA Astrophysics Data System (ADS)

    Tervo, Anu J.; Nyrönen, Tommi H.; Rönkkö, Toni; Poso, Antti

    2003-12-01

    A panel of 92 catechol- O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.

  20. 3D-QSAR, molecular docking and molecular dynamics studies of a series of RORγt inhibitors.

    PubMed

    Wang, Fangfang; Yang, Wei; Shi, Yonghui; Le, Guowei

    2015-09-01

    The discovery of clinically relevant inhibitors of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) for autoimmune diseases therapy has proven to be a challenging task. In the present work, to find out the structural features required for the inhibitory activity, we show for the first time a three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations for a series of novel thiazole/thiophene ketone amides with inhibitory activity at the RORγt receptor. The optimum CoMFA and CoMSIA models, derived from ligand-based superimposition I, exhibit leave-one-out cross-validated correlation coefficient (R(2)cv) of .859 and .805, respectively. Furthermore, the external predictive abilities of the models were evaluated by a test set, producing the predicted correlation coefficient (R(2)pred) of .7317 and .7097, respectively. In addition, molecular docking analysis was applied to explore the binding modes between the inhibitors and the receptor. MD simulation and MM/PBSA method were also employed to study the stability and rationality of the derived conformations, and the binding free energies in detail. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORγt inhibitors with better activity.

  1. An alignment independent 3D QSAR study of the antiproliferative activity of 1,2,4,5-tetraoxanes.

    PubMed

    Cvijetić, Ilija N; Zizak, Zeljko P; Stanojković, Tatjana P; Juranić, Zorica D; Terzić, Natasa; Opsenica, Igor M; Opsenica, Dejan M; Juranić, Ivan O; Drakulić, Branko J

    2010-10-01

    An alignment-free 3D QSAR study on antiproliferative activity of the thirty-three 1,2,4,5-tetraoxane derivatives toward two human dedifferentiated cell lines was reported. GRIND methodology, where descriptors are derived from GRID molecular interaction fields (MIF), were used. It was found that pharmacophoric pattern attributed to the most potent derivatives include amido NH of the primary or secondary amide, and the acetoxy fragments at positions 7 and 12 of steroid core which are, along with the tetraoxane ring, common for all studied compounds. Independently, simple multiple regression model obtained by using the whole-molecular properties, confirmed that the hydrophobicity and the H-bond donor properties are the main parameters influencing potency of compounds toward human cervix carcinoma (HeLa) and human malignant melanoma (FemX) cell lines. Corollary, similar structural motifs are found to be important for the potency toward both examined cell lines.

  2. Structural insights of JAK2 inhibitors: pharmacophore modeling and ligand-based 3D-QSAR studies of pyrido-indole derivatives.

    PubMed

    Gade, Deepak Reddy; Kunala, Pavan; Raavi, Divya; Reddy, Pavan Kumar K; Prasad, Rajendra V V S

    2015-04-01

    In this study we have performed pharmacophore modeling and built a 3D QSAR model for pyrido-indole derivatives as Janus Kinase 2 inhibitors. An efficient pharmacophore has been identified from a data set of 51 molecules and the identified pharmacophore hypothesis consisted of one hydrogen bond acceptor, two hydrogen bond donors and three aromatic rings, i.e. ADDRRR. A powerful 3D-QSAR model has also been constructed by employing Partial Least Square regression analysis with a regression coefficient of 0.97 (R(2)) and Q(2) of 0.95, and Pearson-R of 0.98.

  3. Validation of TZD Scaffold as Potential ARIs: Pharmacophore Modelling, Atom-based 3D QSAR and Docking Studies.

    PubMed

    Dahiya, Lalita; Mahapatra, Manoj Kumar; Kaur, Ramandeep; Kumar, Vipin; Kumar, Manoj

    2017-03-15

    Metabolic disorders associated with diabetic patients are a serious concern. Aldose reductase (ALR2) has been identified as first rate-limiting enzyme in the polyol pathway which catalyzes the reduction of glucose to sorbitol. It represents one of the validated targets to develop potential new chemical entities for the prevention and subsequent progression of microvascular diabetic complications. In order to further understand the intricate structural prerequisites of molecules to act as ALR2 inhibitors, ligand-based pharmacophore model, atom-based 3D-QSAR and structure based drug design studies have been performed on a series of 2,4-thiazolidinedione derivatives with ALR2 inhibitory activity. In the present study, a validated six point pharmacophore model (AAADNR) with three hydrogen bond acceptor (A), one hydrogen bond donor (D), one negative ionic group (N) and one aromatic ring (R) was developed using PHASE module of Schrodinger suite with acceptable PLS statistics (survival score = 3.871, cross-validated correlation coefficient Q2 = 0.6902, correlation coefficient of multiple determination r2 = 0.9019, Pearson-R coefficient = 0.8354 and F distribution = 196.2). In silico predictive studies (pharmacophore modeling, atom-based 3D QSAR and docking combined with drug receptor binding free energetics and pharmacokinetic drug profile) highlighted some of the important structural features of thiazolidinedione analogues required for potential ALR2 inhibitory activity. The result of these studies may account to design a legitimate template for rational drug design of novel, potent and promising ALR2 inhibitors.

  4. 3D-QSAR Studies on a Series of Dihydroorotate Dehydrogenase Inhibitors: Analogues of the Active Metabolite of Leflunomide

    PubMed Central

    Li, Shun-Lai; He, Mao-Yu; Du, Hong-Guang

    2011-01-01

    The active metabolite of the novel immunosuppressive agent leflunomide has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. Self-organizing molecular field analysis (SOMFA), a simple three-dimensional quantitative structure-activity relationship (3D-QSAR) method is used to study the correlation between the molecular properties and the biological activities of a series of analogues of the active metabolite. The statistical results, cross-validated rCV2 (0.664) and non cross-validated r2 (0.687), show a good predictive ability. The final SOMFA model provides a better understanding of DHODH inhibitor-enzyme interactions, and may be useful for further modification and improvement of inhibitors of this important enzyme. PMID:21686163

  5. Azolium analogues as CDK4 inhibitors: Pharmacophore modeling, 3D QSAR study and new lead drug discovery

    NASA Astrophysics Data System (ADS)

    Rondla, Rohini; Padma Rao, Lavanya Souda; Ramatenki, Vishwanath; Vadija, Rajender; Mukkera, Thirupathi; Potlapally, Sarita Rajender; Vuruputuri, Uma

    2017-04-01

    The cyclin-dependent kinase 4 (CDK4) enzyme is a key regulator in cell cycle G1 phase progression. It is often overexpressed in variety of cancer cells, which makes it an attractive therapeutic target for cancer treatment. A number of chemical scaffolds have been reported as CDK4 inhibitors in the literature, and in particular azolium scaffolds as potential inhibitors. Here, a ligand based pharmacophore modeling and an atom based 3D-QSAR analyses for a series of azolium based CDK4 inhibitors are presented. A five point pharmacophore hypothesis, i.e. APRRR with one H-bond acceptor (A), one positive cationic feature (P) and three ring aromatic sites (R) is developed, which yielded an atom based 3D-QSAR model that shows an excellent correlation coefficient value- R2 = 0.93, fisher ratio- F = 207, along with good predictive ability- Q2 = 0.79, and Pearson R value = 0.89. The visual inspection of the 3D-QSAR model, with the most active and the least active ligands, demonstrates the favorable and unfavorable structural regions for the activity towards CDK4. The roles of positively charged nitrogen, the steric effect, ligand flexibility, and the substituents on the activity are in good agreement with the previously reported experimental results. The generated 3D QSAR model is further applied as query for a 3D database screening, which identifies 23 lead drug candidates with good predicted activities and diverse scaffolds. The ADME analysis reveals that, the pharmacokinetic parameters of all the identified new leads are within the acceptable range.

  6. 3D-QSAR and virtual screening studies of thiazolidine-2,4-dione analogs: Validation of experimental inhibitory potencies towards PIM-1 kinase

    NASA Astrophysics Data System (ADS)

    Asati, Vivek; Bharti, Sanjay Kumar; Budhwani, Ashok Kumar

    2017-04-01

    The proviral insertion site in moloney murine leukemia virus (PIM) is a family of serine/threonine kinase of Ca2+-calmodulin-dependent protein kinase (CAMK) group which is responsible for the activation and regulation of cellular transcription and translation. The three isoforms of PIM kinase (PIM-1, PIM-2 and PIM-3) share high homology and functional idleness are widely expressed and involved in a variety of biological processes including cell survival, proliferation, differentiation and apoptosis. Altered expression of PIM-1 kinase correlated with hematologic malignancies and solid tumors. In the present study, atom-based 3D-QSAR, docking and virtual screening studies have been performed on a series of thiazolidine-2,4-dione derivatives as PIM-1 kinase inhibitors. 3D-QSAR and docking approach has shortlisted the most active thiazolidine-2,4-dione derivatives such as 28, 31, 33 and 35 with the incorporation of more than one structural feature in a single molecule. External validations by various parameters and molecular docking studies at the active site of PIM-1 kinase have proved the reliability of the developed 3D-QSAR model. The generated pharmacophore (AADHR.33) from 3D-QSAR study was used for screening of drug like compounds from ZINC database, where ZINC15056464 and ZINC83292944 showed potential binding affinities at the active site amino acid residues (LYS67, GLU171, ASP128 and ASP186) of PIM-1 kinase (PDB ID: "pdb:4DTK").

  7. 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.

  8. DYNAMIC 3D QSAR TECHNIQUES: APPLICATIONS IN TOXICOLOGY

    EPA Science Inventory

    Two dynamic techniques recently developed to account for conformational flexibility of chemicals in 3D QSARs are presented. In addition to the impact of conformational flexibility of chemicals in 3D QSAR models, the applicability of various molecular descriptors is discussed. The...

  9. Molecular docking and 3D-QSAR studies on the binding mechanism of statine-based peptidomimetics with beta-secretase.

    PubMed

    Zuo, Zhili; Luo, Xiaomin; Zhu, Weiliang; Shen, Jianhua; Shen, Xu; Jiang, Hualiang; Chen, Kaixian

    2005-03-15

    beta-Secretase is an important protease in the pathogenesis of Alzheimer's disease. Some statine-based peptidomimetics show inhibitory activities to the beta-secretase. To explore the inhibitory mechanism, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies on these analogues were performed. The Lamarckian Genetic Algorithm (LGA) was applied to locate the binding orientations and conformations of the peptidomimetics with the beta-secretase. A good correlation between the calculated binding free energies and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, highly predictive 3D-QSAR models were developed with q(2) values of 0.582 and 0.622 for CoMFA and CoMSIA, respectively. The predictive abilities of these models were validated by some compounds that were not included in the training set. Furthermore, the 3D-QSAR models were mapped back to the binding site of the beta-secretase, to get a better understanding of vital interactions between the statine-based peptidomimetics and the protease. Both the CoMFA and the CoMSIA field distributions are in well agreement with the structural characteristics of the binding groove of the beta-secretase. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction would be useful in developing new drug leads against Alzheimer's disease.

  10. A Structure-Activity Relationship Study of Imidazole-5-Carboxylic Acid Derivatives as Angiotensin II Receptor Antagonists Combining 2D and 3D QSAR Methods.

    PubMed

    Sharma, Mukesh C

    2016-03-01

    Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationship (QSAR) studies were performed for correlating the chemical composition of imidazole-5-carboxylic acid analogs and their angiotensin II [Formula: see text] receptor antagonist activity using partial least squares and k-nearest neighbor, respectively. For comparing the three different feature selection methods of 2D-QSAR, k-nearest neighbor models were used in conjunction with simulated annealing (SA), genetic algorithm and stepwise coupled with partial least square (PLS) showed variation in biological activity. The statistically significant best 2D-QSAR model having good predictive ability with statistical values of [Formula: see text] and [Formula: see text] was developed by SA-partial least square with the descriptors like [Formula: see text]count, 5Chain count, SdsCHE-index, and H-acceptor count, showing that increase in the values of these descriptors is beneficial to the activity. The 3D-QSAR studies were performed using the SA-PLS. A leave-one-out cross-validated correlation coefficient [Formula: see text] and predicate activity [Formula: see text] = 0.7226 were obtained. The information rendered by QSAR models may lead to a better understanding of structural requirements of substituted imidazole-5-carboxylic acid derivatives and also aid in designing novel potent antihypertensive molecules.

  11. Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2014-08-01

    Farnesoid X receptor (FXR) is a potential therapeutic target for the treatment of diabetes mellitus. Atom-based three-dimensional quantitative structure activity relationship (3D-QSAR) models were developed for a series of 48 benzimidazole-based agonists of FXR. A total of five pharmacophore hypotheses were generated based on the survival score to build QSAR models. HHHRR was considered as a best model that consisted of three hydrophobic features (H) and two aromatic rings (R). The best hypothesis, HHHRR yielded a 3D-QSAR model with good statistical value (R(2)) of 0.8974 for a training set of 39 compounds and also showed good predictive power with correlation coefficient (Q(2)) of 0.7559 for a test set of nine compounds. Furthermore, molecular docking simulation was performed to understand the binding affinity of 48 benzimidazole-based compounds against the active site of human FXR protein. Docking results revealed that both the most active and least active compounds showed similar binding mode to the experimentally observed binding mode of co-crystallized ligand. The generated 3D contour maps revealed the structure activity relationship of the compounds. Substitution effects at different positions of benzimidazole derivatives would lead to the discovery of new agonists against human FXR protein.

  12. Quantitative studies on structure-ORAC relationships of anthocyanins from eggplant and radish using 3D-QSAR.

    PubMed

    Jing, Pu; Zhao, Shujuan; Ruan, Siyu; Sui, Zhongquan; Chen, Lihong; Jiang, Linlei; Qian, Bingjun

    2014-02-15

    The 3-dimensional quantitative structure activity relationship (3D-QSAR) models were established from 21 anthocyanins based on their oxygen radical absorbing capacity (ORAC) and were applied to predict anthocyanins in eggplant and radish for their ORAC values. The cross-validated q(2)=0.857/0.729, non-cross-validated r(2) = 0.958/0.856, standard error of estimate = 0.153/0.134, and F = 73.267/19.247 were for the best QSAR (CoMFA/CoMSIA) models, where the correlation coefficient r(2)pred = 0.998/0.997 (>0.6) indicated a high predictive ability for each. Additionally, the contour map results suggested that structural characteristics of anthocyanins favourable for the high ORAC. Four anthocyanins from eggplant and radish have been screened based on the QSAR models. Pelargonidin-3-[(6''-p-coumaroyl)-glucosyl(2 → 1)glucoside]-5-(6''-malonyl)-glucoside, delphinidin-3-rutinoside-5-glucoside, and delphinidin-3-[(4''-p-coumaroyl)-rhamnosyl(1 → 6)glucoside]-5-glucoside potential with high ORAC based the QSAR models were isolated and also confirmed for their relative high antioxidant ability, which might attribute to the bulky and/or electron-donating substituent at the 3-position in the C ring or/and hydrogen bond donor group/electron donating group on the R1 position in the B ring.

  13. Pharmacophore modeling and atom-based 3D-QSAR studies on amino derivatives of indole as potent isoprenylcysteine carboxyl methyltransferase (Icmt) inhibitors

    NASA Astrophysics Data System (ADS)

    Bhadoriya, Kamlendra Singh; Sharma, Mukesh C.; Jain, Shailesh V.

    2015-02-01

    Icmt enzymes are of particular importance in the post-translational modification of proteins that are involved in the regulation of cell growth. Thus, effective Icmt inhibitors may be of significant therapeutic importance in oncogenesis. To determine the structural requirements responsible for high affinity of previously reported amino derivatives of indole as Icmt inhibitors, a successful pharmacophore generation and atom-based 3D-QSAR analysis have been carried out. The best four-point pharmacophore model with four features HHRR: two hydrophobic groups (H) and two aromatic rings (R) as pharmacophore features was developed by PHASE module of Schrodinger suite. In this study, highly predictive 3D-QSAR models have been developed for Icmt inhibition using HHRR.191 hypothesis. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The validation of the PHASE model was done by dividing the dataset into training and test set. The statistically significant the four-point pharmacophore hypothesis yielded a 3D-QSAR model with good PLS statistics results (R2 = 0.9387, Q2 = 0.8132, F = 114.8, SD = 0.1567, RMSE = 0.2682, Pearson-R = 0.9147). The generated model showed excellent predictive power, with a correlation coefficient of Q2 = 0.8132. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR provide detailed structural insights as well as highlights important binding features of novel amino derivatives of indole as Icmt inhibitors which can afford guidance for the rational drug design of novel, potent and promising Icmt inhibitors with enhanced potencies and may prove helpful for further lead optimization and virtual screening.

  14. 3-Heterocycle-phenyl N-alkylcarbamates as FAAH inhibitors: design, synthesis and 3D-QSAR studies.

    PubMed

    Käsnänen, Heikki; Myllymäki, Mikko J; Minkkilä, Anna; Kataja, Antti O; Saario, Susanna M; Nevalainen, Tapio; Koskinen, Ari M P; Poso, Antti

    2010-02-01

    Carbamates are a well-established class of fatty acid amide hydrolase (FAAH) inhibitors. Here we describe the synthesis of meta-substituted phenolic N-alkyl/aryl carbamates and their in vitro FAAH inhibitory activities. The most potent compound, 3-(oxazol-2yl)phenyl cyclohexylcarbamate (2 a), inhibited FAAH with a sub-nanomolar IC(50) value (IC(50)=0.74 nM). Additionally, we developed and validated three-dimensional quantitative structure-activity relationships (QSAR) models of FAAH inhibition combining the newly disclosed carbamates with our previously published inhibitors to give a total set of 99 compounds. Prior to 3D-QSAR modeling, the degree of correlation between FAAH inhibition and in silico reactivity was also established. Both 3D-QSAR methods used, CoMSIA and GRID/GOLPE, produced statistically significant models with coefficient of correlation for external prediction (R(2) (PRED)) values of 0.732 and 0.760, respectively. These models could be of high value in further FAAH inhibitor design.

  15. Molecular docking and 3D-QSAR studies on the glucocorticoid receptor antagonistic activity of hydroxylated polychlorinated biphenyls.

    PubMed

    Liu, S; Luo, Y; Fu, J; Zhou, J; Kyzas, G Z

    2016-01-01

    The glucocorticoid receptor (GR) antagonistic activities of hydroxylated polychlorinated biphenyls (HO-PCBs) were recently characterised. To further explore the interactions between HO-PCBs and the GR, and to elucidate structural characteristics that influence the GR antagonistic activity of HO-PCBs, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Comparative molecular similarity indices analysis (CoMSIA) was performed using both ligand- and receptor-based alignment schemes. Results generated from the receptor-based model were found to be more satisfactory, with q(2) of 0.632 and r(2) of 0.931 compared with those from the ligand-based model. Some internal validation strategies (e.g. cross-validation analysis, bootstrapping analysis and Y-randomisation) and an external validation method were used respectively to further assess the stability and predictive ability of the derived model. Graphical interpretation of the model provided some insights into the structural features that affected the GR antagonistic activity of HO-PCBs. Molecular docking studies revealed that some key residues were critical for ligand-receptor interactions by forming hydrogen bonds (Glu540) and hydrophobic interactions with ligands (Ile539, Val543 and Trp577). Although CoMSIA sometimes depends on the alignment of the molecules, the information provided is beneficial for predicting the GR antagonistic activities of HO-PCB homologues and is helpful for understanding the binding mechanisms of HO-PCBs to GR.

  16. Optimization, pharmacophore modeling and 3D-QSAR studies of sipholanes as breast cancer migration and proliferation inhibitors.

    PubMed

    Foudah, Ahmed I; Sallam, Asmaa A; Akl, Mohamed R; El Sayed, Khalid A

    2014-02-12

    Sipholenol A, a triterpene isolated from the Red Sea sponge Callyspongia siphonella, was previously shown to reverse multidrug resistance in P-glycoprotein-overexpressing cancer cells. Moreover, sipholanes showed promising in vitro inhibitory effects against the invasion and migration of the metastatic human breast cancer cell line MDA-MB-231. The breast tumor kinase (Brk), a mediator of cancer cell phenotypes important for proliferation, survival, and migration, was proposed as a potential target. This study reports additional semisynthetic optimization of sipholenol A esters to improve the breast cancer antimigratory and antiproliferative activities as well as Brk phosphorylation inhibition. Fifteen new sipholenol A analogs (25-39) were semisynthesized. Sipholenol A 4β-4',5'-dichlorobenzoate ester (29) was the most potent, with an IC50 value of 1.3 μM in the migration assay. The level of Brk phosphorylation inhibition of 29 was assessed using the Z'-LYTE™ kinase assay and Western blot analysis. Active analogs showed no toxicity on the non-tumorigenic epithelial breast cell line MCF10A at doses equal to their IC50 values or higher in migration and proliferation assays, suggesting their selectivity towards malignant cells. Pharmacophore modeling and 3D-QSAR studies were conducted to identify important pharmacophoric features and correlate 3D-chemical structure with activity. These studies provided the evidence for future design of novel antimigratory compounds based on a simplified sipholane structure possessing rings A and B (perhydrobenzoxepine) connected to substituted aromatic esters, with the elimination of rings C and D ([5,3,0]bicyclodecane system). This will enable the future synthesis of the new active entities feasibly and cost-effectively. These results demonstrate the potential of marine natural products for the discovery of novel scaffolds for the control and management of metastatic breast cancer.

  17. 2D, 3D-QSAR and docking studies of 1,2,3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors

    PubMed Central

    2012-01-01

    Background The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors, the quantitative structure–activity relationship (QSAR) approach became very useful and largely widespread technique forligand-based drug design. Methods We perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-thiadiazole thioacetanilides analogues to elucidate the structural properties required for HIV-RT inhibitory activity. Results The 2D-QSAR studies were performed using multiple linear regression method, giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2 = 0.89 and a non-cross-validated correlation coefficient r2 = 0.97 were obtained. Docking analysis suggests that the new series have comparable binding affinity with the standard compounds. Conclusions This approach showed that hydrophobic and electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs. PMID:22691718

  18. 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.

  19. In silico exploration of c-KIT inhibitors by pharmaco-informatics methodology: pharmacophore modeling, 3D QSAR, docking studies, and virtual screening.

    PubMed

    Chaudhari, Prashant; Bari, Sanjay

    2016-02-01

    c-KIT is a component of the platelet-derived growth factor receptor family, classified as type-III receptor tyrosine kinase. c-KIT has been reported to be involved in, small cell lung cancer, other malignant human cancers, and inflammatory and autoimmune diseases associated with mast cells. Available c-KIT inhibitors suffer from tribulations of growing resistance or cardiac toxicity. A combined in silico pharmacophore and structure-based virtual screening was performed to identify novel potential c-KIT inhibitors. In the present study, five molecules from the ZINC database were retrieved as new potential c-KIT inhibitors, using Schrödinger's Maestro 9.0 molecular modeling suite. An atom-featured 3D QSAR model was built using previously reported c-KIT inhibitors containing the indolin-2-one scaffold. The developed 3D QSAR model ADHRR.24 was found to be significant (R2 = 0.9378, Q2 = 0.7832) and instituted to be sufficiently robust with good predictive accuracy, as confirmed through external validation approaches, Y-randomization and GH approach [GH score 0.84 and Enrichment factor (E) 4.964]. The present QSAR model was further validated for the OECD principle 3, in that the applicability domain was calculated using a "standardization approach." Molecular docking of the QSAR dataset molecules and final ZINC hits were performed on the c-KIT receptor (PDB ID: 3G0E). Docking interactions were in agreement with the developed 3D QSAR model. Model ADHRR.24 was explored for ligand-based virtual screening followed by in silico ADME prediction studies. Five molecules from the ZINC database were obtained as potential c-KIT inhibitors with high in -silico predicted activity and strong key binding interactions with the c-KIT receptor.

  20. 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.

  1. Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β

    SciTech Connect

    Li, Xiaolin; Ye, Li; Wang, Xiaoxiang; Wang, Xinzhou; Liu, Hongling; Zhu, Yongliang; Yu, Hongxia

    2012-12-15

    Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q{sup 2}) was 0.571 and non-cross-validation correlation coefficient (r{sup 2}) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results. -- Highlights: ► The thyroid hormone activities of HO-PBDEs were studied by 3D-QSAR. ► The binding modes between HO-PBDEs and TRβ were explored. ► 3D-QSAR, molecular docking, and molecular dynamics (MD) methods were performed.

  2. Design, synthesis and 3D-QSAR studies of novel 1,4-dihydropyridines as TGFβ/Smad inhibitors.

    PubMed

    Längle, Daniel; Marquardt, Viktoria; Heider, Elena; Vigante, Brigita; Duburs, Gunars; Luntena, Iveta; Flötgen, Dirk; Golz, Christopher; Strohmann, Carsten; Koch, Oliver; Schade, Dennis

    2015-05-05

    Targeting TGFβ/Smad signaling is an attractive strategy for several therapeutic applications given its role as a key player in many pathologies, including cancer, autoimmune diseases and fibrosis. The class of b-annelated 1,4-dihydropyridines (DHPs) represents promising novel pharmacological tools as they interfere with this pathway in a novel fashion, i.e. through induction of TGFβ receptor type II degradation. In the present work, >40 rationally designed, novel DHPs were synthesized and evaluated for TGFβ inhibition, substantially expanding the current understanding of the SAR profile. Key findings include that the 2-position tolerates a wide variety of polar functionalities, suggesting that this region could possibly be solvent-exposed within the (thus far) unknown cellular target. A structural explanation for pathway selectivity is provided based on a diverse series of 4″-substituted DHPs, including molecular electrostatic potential (MEP) calculations. Moreover, the absolute configuration for the chiral 4-position was determined by X-ray crystal analysis and revealed that the bioactive (+)-enantiomers are (R)-configured. Another key objective was to establish a 3D-QSAR model which turned out to be robust (r(2) = 0.93) with a good predictive power (r(2)pred = 0.69). This data further reinforces the hypothesis that this type of DHPs exerts its novel TGFβ inhibitory mode of action through binding a distinct target and that unspecific activities that would derive from intrinsic properties of the ligands (e.g., lipophilicity) play a negligible role. Therefore, the present study provides a solid basis for further ligand-based design of additional analogs or DHP scaffold-derived compounds for hit-to-lead optimization, required for more comprehensive pharmacological studies in vivo.

  3. Pharmacophore modelling and atom-based 3D-QSAR studies on N-methyl pyrimidones as HIV-1 integrase inhibitors.

    PubMed

    Reddy, Karnati Konda; Singh, Sanjeev Kumar; Dessalew, Nigus; Tripathi, Sunil Kumar; Selvaraj, Chandrabose

    2012-06-01

    Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to N-methyl pyrimidones as HIV-1 integrase inhibitors. Based on the ligand-based pharmacophore model, we got 5-point pharmacophore model AADDR, with two hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R). The generated pharmacophore-based alignment was used to derive a predictive atom-based 3D-QSAR model for the training set (r(2) = 0.92, SD = 0.16, F = 84.8, N = 40) and for test set (Q(2) = 0.71, RMSE = 0.06, Pearson R = 0.90, N = 10). From these results, AADDR pharmacophore feature was selected as best common pharmacophore hypothesis, and atom-based 3D-QSAR results also support the outcome by means of favourable and unfavourable regions of hydrophobic and electron-withdrawing groups for the most potent compound 30. These results can be useful for further design of new and potent HIV-1 IN inhibitors.

  4. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-11-01

    Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2 )= .9949), cross validation coefficient (Q(2 )= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity.

  5. In silico study on β-aminoketone derivatives as thyroid hormone receptor inhibitors: a combined 3D-QSAR and molecular docking study.

    PubMed

    Wang, Fang-Fang; Yang, Wei; Shi, Yong-Hui; Le, Guo-Wei

    2016-12-01

    In order to explore the structure-activity correlation of a series of β-aminoketone analogs as inhibitors of thyroid hormone receptor (TR), a set of three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), for the first time, were developed in the present work. The best CoMFA model with steric and electrostatic fields exhibited [Formula: see text], [Formula: see text] for TRβ, and [Formula: see text], [Formula: see text] for TRα. 3D contour maps produced from the optimal models were further analyzed individually, which provide the areas in space where interactive fields would affect the inhibitory activity. In addition, the binding modes of inhibitors at the active site of TRs were examined using molecular docking, the results indicated that this series of inhibitors fit into the active site of TRs by forming hydrogen bonding and electrostatic interactions. The docking studies also revealed that Leu305, Val458 for TRβ, and Asp407 for TRα are showing hydrogen bonds with the most active inhibitors. In any case, the 3D-QSAR models combined with the binding information will serve as a useful approach to explore the chemical space for improving the activity of TRβ and TRα inhibitors.

  6. 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.

  7. 3D-QSAR and molecular docking studies of selective agonists for the thyroid hormone receptor beta.

    PubMed

    Du, Juan; Qin, Jin; Liu, Huanxiang; Yao, Xiaojun

    2008-09-01

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) on a series of agonists of thyroid hormone receptor beta (TRbeta), which may lead to safe therapies for non-thyroid disorders while avoiding the cardiac side effects. The reasonable q(2) (cross-validated) values 0.600 and 0.616 and non-cross-validated r(2) values of 0.974 and 0.974 were obtained for CoMFA and CoMSIA models for the training set compounds, respectively. The predictive ability of two models was validated using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)(2)) of 0.688 and 0.674, respectively. The Lamarckian Genetic Algorithm (LGA) of AutoDock 4.0 was employed to explore the binding mode of the compound at the active site of TRbeta. The results not only lead to a better understanding of interactions between these agonists and the thyroid hormone receptor beta but also can provide us some useful information about the influence of structures on the activity which will be very useful for designing some new agonist with desired activity.

  8. A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study.

    PubMed

    Choubey, Sanjay K; Jeyaraman, Jeyakanthan

    2016-11-01

    Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r(2)=0.82 and cross validation correlation co-efficient q(2)=0.70. External validation result displays high predictive power with r(2) (o) value of 0.88 and r(2) (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein.

  9. Combined 3D-QSAR modeling and molecular docking studies on pyrrole-indolin-2-ones as Aurora A kinase inhibitors.

    PubMed

    Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

    2011-01-01

    Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r(2) (cv) values of 0.726 and 0.566, and r(2) values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.

  10. 3D-QSAR study and design of 4-hydroxyamino α-pyranone carboxamide analogues as potential anti-HCV agents

    NASA Astrophysics Data System (ADS)

    Li, Wenlian; Xiao, Faqi; Zhou, Mingming; Jiang, Xuejin; Liu, Jun; Si, Hongzong; Xie, Meng; Ma, Xiuting; Duan, Yunbo; Zhai, Honglin

    2016-09-01

    The three dimensional-quantitative structure activity relationship (3D-QSAR) study was performed on a series of 4-hydroxyamino α-pyranone carboxamide analogues using comparative molecular similarity indices analysis (COMSIA). The purpose of the present study was to develop a satisfactory model providing a reliable prediction based on 4-hydroxyamino α-pyranone carboxamide analogues as anti-HCV (hepatitis C virus) inhibitors. The statistical results and the results of validation of this optimum COMSIA model were satisfactory. Furthermore, analysis of the contour maps helped to provide guidelines for finding structural requirement. Therefore, the satisfactory results from this study may provide useful guidelines for drug development of anti-HCV inhibitors.

  11. In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations.

    PubMed

    Gao, Xiaodong; Han, Liping; Ren, Yujie

    2016-05-05

    Checkpoint kinase 1 (Chk1) is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q² values (0.531, 0.726), fitted correlation r² coefficients (higher than 0.90), and standard error of prediction (less than 0.250). These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.

  12. Free energy force field (FEFF) 3D-QSAR analysis of a set of Plasmodium falciparum dihydrofolate reductase inhibitors

    NASA Astrophysics Data System (ADS)

    Santos-Filho, Osvaldo A.; Mishra, Rama K.; Hopfinger, A. J.

    2001-09-01

    Free energy force field (FEFF) 3D-QSAR analysis was used to construct ligand-receptor binding models for a set of 18 structurally diverse antifolates including pyrimethamine, cycloguanil, methotrexate, aminopterin and trimethoprim, and 13 pyrrolo[2,3-d]pyrimidines. The molecular target (`receptor') used was a 3D-homology model of a specific mutant type of Plasmodium falciparum (Pf) dihydrofolate reductase (DHFR). The dependent variable of the 3D-QSAR models is the IC50 inhibition constant for the specific mutant type of PfDHFR. The independent variables of the 3D-QSAR models (the descriptors) are scaled energy terms of a modified first-generation AMBER force field combined with a hydration shell aqueous solvation model and a collection of 2D-QSAR descriptors often used in QSAR studies. Multiple temperature molecular dynamics simulation (MDS) and the genetic function approximation (GFA) were employed using partial least square (PLS) and multidimensional linear regressions as the fitting functions to develop FEFF 3D-QSAR models for the binding process. The significant FEFF energy terms in the best 3D-QSAR models include energy contributions of the direct ligand-receptor interaction. Some changes in conformational energy terms of the ligand due to binding to the enzyme are also found to be important descriptors. The FEFF 3D-QSAR models indicate some structural features perhaps relevant to the mechanism of resistance of the PfDHFR to current antimalarials. The FEFF 3D-QSAR models are also compared to receptor-independent (RI) 4D-QSAR models developed in an earlier study and subsequently refined using recently developed generalized alignment rules.

  13. 3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

    NASA Astrophysics Data System (ADS)

    Li, Wenlian; Si, Hongzong; Li, Yang; Ge, Cuizhu; Song, Fucheng; Ma, Xiuting; Duan, Yunbo; Zhai, Honglin

    2016-08-01

    Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion and hepatitis C virus (HCV) infection is a global health threat. The HCV NS5B polymerase, an RNA dependent RNA polymerase (RdRp) and an essential role in the replication of the virus, has no functional equivalent in mammalian cells. So the research and development of efficient NS5B polymerase inhibitors provides a great strategy for antiviral therapy against HCV. A combined three-dimensional quantitative structure-activity relationship (QSAR) modeling was accomplished to profoundly understand the structure-activity correlation of a train of indole-based inhibitors of the HCV NS5B polymerase to against HCV. A comparative molecular similarity indices analysis (COMSIA) model as the foundation of the maximum common substructure alignment was developed. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.627 and non-cross-validated r2 value was 0.943. In addition, the results of internal validations of bootstrapping and Y-randomization confirmed the rationality and good predictive ability of the model, as well as external validation (the external predictive correlation coefficient rext2 = 0.629). The information obtained from the COMSIA contour maps enables the interpretation of their structure-activity relationship. Furthermore, the molecular docking study of the compounds for 3TYV as the protein target revealed important interactions between active compounds and amino acids, and several new potential inhibitors with higher activity predicted were designed basis on our analyses and supported by the simulation of molecular docking. Meanwhile, the OSIRIS Property Explorer was introduced to help select more satisfactory compounds. The satisfactory results from this study may lay a reliable theoretical base for drug development of hepatitis C virus NS5B polymerase inhibitors.

  14. 3D-QSAR studies on unsaturated 4-azasteroids as human 5alpha-reductase inhibitors: a self organizing molecular field analysis approach.

    PubMed

    Aggarwal, Saurabh; Thareja, Suresh; Bhardwaj, T R; Kumar, Manoj

    2010-02-01

    Azasteroids have been reported as inhibitors of human 5alpha-reductase enzyme. These were designed by substitution of one carbon atom of steroidal A ring by heteroatom nitrogen. Due to lack of information on the crystal structure of human 5alpha-reductase, 3D-QSAR study has been performed on a series of unsaturated 4-azasteroids using Self Organizing Molecular Field Analysis (SOMFA) for rationalizing the molecular properties and human 5alpha-reductase inhibitory activities. The statistical results having good cross-validated r(2)(cv) (0.783), non cross-validated r(2) (0.806) and F-test value (87.282), showed satisfied predictive ability. Analysis of SOMFA models through electrostatic and shape grids provide useful information for the design and optimization of new steroidal human 5alpha-reductase inhibitors.

  15. 2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human β₃-Adrenergic Activity.

    PubMed

    Apablaza, Gastón; Montoya, Luisa; Morales-Verdejo, Cesar; Mellado, Marco; Cuellar, Mauricio; Lagos, Carlos F; Soto-Delgado, Jorge; Chung, Hery; Pessoa-Mahana, Carlos David; Mella, Jaime

    2017-03-05

    The β₃ adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new β₃ adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent β₃ adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving β₃ adrenergic activity is given.

  16. 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.

  17. 3D-QSAR-Assisted Design, Synthesis, and Evaluation of Novobiocin Analogues

    PubMed Central

    2012-01-01

    Hsp90 is an attractive therapeutic target for the treatment of cancer. Extensive structural modifications to novobiocin, the first Hsp90 C-terminal inhibitor discovered, have produced a library of novobiocin analogues and revealed some structure–activity relationships. On the basis of the most potent novobiocin analogues generated from prior studies, a three-dimensional quantitative structure–activity (3D QSAR) model was built. In addition, a new set of novobiocin analogues containing various structural features supported by the 3D QSAR model were synthesized and evaluated against two breast cancer cell lines. Several new inhibitors produced antiproliferative activity at midnanomolar concentrations, which results through Hsp90 inhibition. PMID:23606927

  18. Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling

    NASA Astrophysics Data System (ADS)

    Cappel, Daniel; Dixon, Steven L.; Sherman, Woody; Duan, Jianxin

    2015-02-01

    3-D ligand conformations are required for most ligand-based drug design methods, such as pharmacophore modeling, shape-based screening, and 3-D QSAR model building. Many studies of conformational search methods have focused on the reproduction of crystal structures (i.e. bioactive conformations); however, for ligand-based modeling the key question is how to generate a ligand alignment that produces the best results for a given query molecule. In this work, we study different conformation generation modes of ConfGen and the impact on virtual screening (Shape Screening and e-Pharmacophore) and QSAR predictions (atom-based and field-based). In addition, we develop a new search method, called common scaffold alignment, that automatically detects the maximum common scaffold between each screening molecule and the query to ensure identical coordinates of the common core, thereby minimizing the noise introduced by analogous parts of the molecules. In general, we find that virtual screening results are relatively insensitive to the conformational search protocol; hence, a conformational search method that generates fewer conformations could be considered "better" because it is more computationally efficient for screening. However, for 3-D QSAR modeling we find that more thorough conformational sampling tends to produce better QSAR predictions. In addition, significant improvements in QSAR predictions are obtained with the common scaffold alignment protocol developed in this work, which focuses conformational sampling on parts of the molecules that are not part of the common scaffold.

  19. Use of molecular modeling, docking, and 3D-QSAR studies for the determination of the binding mode of benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors.

    PubMed

    Kim, Ki Hwan; Gaisina, Irina; Gallier, Franck; Holzle, Denise; Blond, Sylvie Y; Mesecar, Andrew; Kozikowski, Alan P

    2009-12-01

    Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3beta (GSK-3beta) inhibitors. The approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3beta are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC(50) values has the following statistics: R(2)(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R(2) = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R(2) = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3beta. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.

  20. 3D-QSAR and docking studies of 3-Pyridine heterocyclic derivatives as potent PI3K/mTOR inhibitors

    NASA Astrophysics Data System (ADS)

    Yang, Wenjuan; Shu, Mao; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Meng, Lingxin; Lin, Zhihua

    2013-12-01

    Phosphoinosmde-3-kinase/ mammalian target of rapamycin (PI3K/mTOR) dual inhibitors have attracted a great deal of interest as antitumor drugs research. In order to design and optimize these dual inhibitors, two types of 3D-quantitative structure-activity relationship (3D-QSAR) studies based on the ligand alignment and receptor alignment were applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). In the study based on ligands alignment, models of PI3K (CoMFA with r2, 0.770; q2, 0.622; CoMSIA with r2, 0.945; q2, 0.748) and mTOR (CoMFA with r2, 0.850; q2, 0.654; CoMSIA with r2, 0.983; q2, 0.676) have good predictability. And in the study based on receptor alignment, models of PI3K (CoMFA with r2, 0.745; q2, 0.538; CoMSIA with r2, 0.938; q2, 0.630) and mTOR (CoMFA with r2, 0.977; q2, 0.825; CoMSIA with r2, 0.985; q2, 0.728) also have good predictability. 3D contour maps and docking results suggested different groups on the core parts of the compounds could enhance the biological activities. Finally, ten derivatives as potential candidates of PI3K/mTOR inhibitors with good predicted activities were designed.

  1. 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.

  2. Combined pharmacophore and 3D-QSAR study on a series of Staphylococcus aureus Sortase A inhibitors.

    PubMed

    Uddin, Reaz; Lodhi, Mazhar U; Ul-Haq, Zaheer

    2012-08-01

    Methicillin resistant Staphylococcus aureus has become a major health concern and it requires new therapeutic agents. Staphylococcus aureus Sortase A enzyme contributes in adherence of bacteria with the cell wall of host cell; consequently, inhibition of S. aureus Sortase A by small molecules could be employed as potential antibacterial agents against methicillin resistant S. aureus. Current study focused on the identification of 3D pharmacophoric features within a series of rhodanine, pyridazinone, and pyrazolethione analogs as S. aureus Sortase A inhibitors. Pharmacophore model was constructed employing representative molecules using Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database. The identified pharmacophoric points were then utilized to create alignment hypothesis for three-dimensional quantitative structure-activity relationships. Outcome of comparative molecular field analysis and comparative molecular similarity indices analysis experiments were in good agreement (comparative molecular field analysis: q(2) = 0.562 and r(2) = 0.995, comparative molecular similarity indices analysis: q(2) = 0.549 and r(2) = 0.978) and capable of explaining the variance in biological activities coherently with respect to the structural features of compounds. The results were also found in concurrence with the outcome of pharmacophoric features.

  3. 3-D QSAutogrid/R: an alternative procedure to build 3-D QSAR models. Methodologies and applications.

    PubMed

    Ballante, Flavio; Ragno, Rino

    2012-06-25

    Since it first appeared in 1988 3-D QSAR has proved its potential in the field of drug design and activity prediction. Although thousands of citations now exist in 3-D QSAR, its development was rather slow with the majority of new 3-D QSAR applications just extensions of CoMFA. An alternative way to build 3-D QSAR models, based on an evolution of software, has been named 3-D QSAutogrid/R and has been developed to use only software freely available to academics. 3-D QSAutogrid/R covers all the main features of CoMFA and GRID/GOLPE with implementation by multiprobe/multiregion variable selection (MPGRS) that improves the simplification of interpretation of the 3-D QSAR map. The methodology is based on the integration of the molecular interaction fields as calculated by AutoGrid and the R statistical environment that can be easily coupled with many free graphical molecular interfaces such as UCSF-Chimera, AutoDock Tools, JMol, and others. The description of each R package is reported in detail, and, to assess its validity, 3-D QSAutogrid/R has been applied to three molecular data sets of which either CoMFA or GRID/GOLPE models were reported in order to compare the results. 3-D QSAutogrid/R has been used as the core engine to prepare more that 240 3-D QSAR models forming the very first 3-D QSAR server ( www.3d-qsar.com ) with its code freely available through R-Cran distribution.

  4. 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.

  5. 3D QSAR STUDIES ON A SERIES OF QUINAZOLINE DERRIVATIVES AS TYROSINE KINASE (EGFR) INHIBITOR: THE K-NEAREST NEIGHBOR MOLECULAR FIELD ANALYSIS APPROACH

    PubMed Central

    Noolvi, Malleshappa N.; Patel, Harun M.

    2010-01-01

    Epidermal growth factor receptor (EGFR) protein tyrosine kinases (PTKs) are known for its role in cancer. Quinazoline have been reported to be the molecules of interest, with potent anticancer activity and they act by binding to ATP site of protein kinases. ATP binding site of protein kinases provides an extensive opportunity to design newer analogs. With this background, we report an attempt to discern the structural and physicochemical requirements for inhibition of EGFR tyrosine kinase. The k-Nearest Neighbor Molecular Field Analysis (kNN-MFA), a three dimensional quantitative structure activity relationship (3D- QSAR) method has been used in the present case to study the correlation between the molecular properties and the tyrosine kinase (EGFR) inhibitory activities on a series of quinazoline derivatives. kNNMFA calculations for both electrostatic and steric field were carried out. The master grid maps derived from the best model has been used to display the contribution of electrostatic potential and steric field. The statistical results showed significant correlation coefficient r2 (q2) of 0.846, r2 for external test set (pred_r2) 0.8029, coefficient of correlation of predicted data set (pred_r2se) of 0.6658, degree of freedom 89 and k nearest neighbor of 2. Therefore, this study not only casts light on binding mechanism between EGFR and its inhibitors, but also provides hints for the design of new EGFR inhibitors with observable structural diversity PMID:24825983

  6. 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.

  7. 3D-QSAR Studies on Barbituric Acid Derivatives as Urease Inhibitors and the Effect of Charges on the Quality of a Model

    PubMed Central

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

    2016-01-01

    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. PMID:27144563

  8. Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques.

    PubMed

    Wang, Jing Li; Cheng, Li Ping; Wang, Tian Chi; Deng, Wei; Wu, Fan Hong

    2017-03-01

    To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q(2)) and non-cross-validated correlation coefficient (r(2)) of the best CoMFA model are 0.715 and 0.992, respectively. The q(2) and r(2) values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.

  9. 3D-QSAR and molecular modeling studies on 2,3-dideoxy hexenopyranosid-4-uloses as anti-tubercular agents targeting alpha-mannosidase.

    PubMed

    Shah, Priyanka; Saquib, Mohammad; Sharma, Smriti; Husain, Irfan; Sharma, Sandeep K; Singh, Vinayak; Srivastava, Ranjana; Shaw, Arun K; Siddiqi, Mohammad Imran

    2015-04-01

    Ligand-based and structure-based methods were applied in combination to exploit the physicochemical properties of 2,3-dideoxy hex-2-enopyranosid-4-uloses against Mycobacterium tuberculosis H37Rv. Statistically valid 3D-QSAR models with good correlation and predictive power were obtained with CoMFA steric and electrostatic fields (r(2) = 0.797, q(2) = 0.589) and CoMSIA with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r(2) = 0.867, q(2) = 0.570) based on training set of 33 molecules with predictive r(2) of 0.808 and 0.890 for CoMFA and CoMSIA respectively. The results illustrate the requirement of optimal alkyl chain length at C-1 position and acceptor groups along hydroxy methyl substituent of C-6 to enhance the anti-tubercular activity of the 2,3-dideoxy hex-2-enopyranosid-4-uloses while any substitution at C-3 position exert diminishing effect on anti-tubercular activity of these enulosides. Further, homology modeling of M. tuberculosis alpha-mannosidase followed by molecular docking and molecular dynamics simulations on co-complexed models were performed to gain insight into the rationale for binding affinity of selected inhibitors with the target of interest. The comprehensive information obtained from this study will help to better understand the structural basis of biological activity of this class of molecules and guide further design of more potent analogues as anti-tubercular agents.

  10. Combined CoMFA and CoMSIA 3D-QSAR study of benzimidazole and benzothiophene derivatives with selective affinity for the CB2 cannabinoid receptor.

    PubMed

    Romero-Parra, Javier; Chung, Hery; Tapia, Ricardo A; Faúndez, Mario; Morales-Verdejo, Cesar; Lorca, Marcos; Lagos, Carlos F; Di Marzo, Vincenzo; David Pessoa-Mahana, C; Mella, Jaime

    2017-04-01

    The preceding years have brought an exponential increase in our understanding of the endocannabinoid system (ECS), including the knowledge of CB1 and CB2 cannabinoid receptors, endocannabinoids, and the enzymes that synthesize and degrade endocannabinoids. Among these ECS components CB2 receptors have been the subject of considerable attention, primarily due to their promising therapeutic potential to treat numerous pathologies while avoiding the adverse psychotropic effects that can accompany CB1 receptor-based therapies. Recently, our research group has reported a new series of non-cytotoxic benzo[d]imidazoles and benzo[b]thiophenes displaying high CB2/CB1 selectivity index. In order to investigate the structural requirements for CB2 ligands and to derive a predictive model that can be used for the design of novel selective CB2 ligands, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on the above mentioned chemical series employing comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques. The CoMFA and CoMSIA models displayed high external predictability (rpred(2) 0.919 and 0.908) and good statistical robustness. Valuable information regarding the steric, electrostatic and hydrophobic properties of the molecules was obtained, and several modifications around both heterocycles were evaluated with the aim to generate new promising series of benzo[d]imidazoles and benzo[b]thiophenes derivatives displaying high CB2 selectivity and low toxicity.

  11. Structure/response correlations and similarity/diversity analysis by GETAWAY descriptors. 2. Application of the novel 3D molecular descriptors to QSAR/QSPR studies.

    PubMed

    Consonni, Viviana; Todeschini, Roberto; Pavan, Manuela; Gramatica, Paola

    2002-01-01

    In a previous paper the theory of the new molecular descriptors called GETAWAY (GEometry, Topology, and Atom-Weights AssemblY) was explained. These descriptors have been proposed with the aim of matching 3D-molecular geometry, atom relatedness, and chemical information. In this paper prediction ability in structure-property correlations of GETAWAY descriptors has been tested extensively by analyzing the regressions of these descriptors for selected properties of some reference compound classes. Moreover, the general performance of the new descriptors in QSAR/QSPR has been evaluated with respect to other well-known sets of molecular descriptors.

  12. Molecular modeling studies on series of Btk inhibitors using docking, structure-based 3D-QSAR and molecular dynamics simulation: a combined approach.

    PubMed

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

    2016-03-01

    Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q (2) = 0.675, NOC = 5, r (2) = 0.961) and COMSIA (q (2) = 0.704, NOC = 6, r (2) = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm (2) metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.

  13. Fragment-based strategy for structural optimization in combination with 3D-QSAR.

    PubMed

    Yuan, Haoliang; Tai, Wenting; Hu, Shihe; Liu, Haichun; Zhang, Yanmin; Yao, Sihui; Ran, Ting; Lu, Shuai; Ke, Zhipeng; Xiong, Xiao; Xu, Jinxing; Chen, Yadong; Lu, Tao

    2013-10-01

    Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure-activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets.

  14. Fragment-based strategy for structural optimization in combination with 3D-QSAR

    NASA Astrophysics Data System (ADS)

    Yuan, Haoliang; Tai, Wenting; Hu, Shihe; Liu, Haichun; Zhang, Yanmin; Yao, Sihui; Ran, Ting; Lu, Shuai; Ke, Zhipeng; Xiong, Xiao; Xu, Jinxing; Chen, Yadong; Lu, Tao

    2013-10-01

    Fragment-based drug design has emerged as an important methodology for lead discovery and drug design. Different with other studies focused on fragment library design and active fragment identification, a fragment-based strategy was developed in combination with three-dimensional quantitative structure-activity relationship (3D-QSAR) for structural optimization in this study. Based on a validated scaffold or fragment hit, a series of structural optimization was conducted to convert it to lead compounds, including 3D-QSAR modelling, active site analysis, fragment-based structural optimization and evaluation of new molecules. 3D-QSAR models and active site analysis provided sufficient information for confirming the SAR and pharmacophoric features for fragments. This strategy was evaluated through the structural optimization on a c-Met inhibitor scaffold 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one, which resulted in an c-Met inhibitor with high inhibitory activity. Our study suggested the effectiveness of this fragment-based strategy and the druggability of our newly explored active region. The reliability of this strategy indicated it could also be applied to facilitate lead optimization of other targets.

  15. Development of biologically active compounds by combining 3D QSAR and structure-based design methods

    NASA Astrophysics Data System (ADS)

    Sippl, Wolfgang

    2002-11-01

    One of the major challenges in computational approaches to drug design is the accurate prediction of the binding affinity of novel biomolecules. In the present study an automated procedure which combines docking and 3D-QSAR methods was applied to several drug targets. The developed receptor-based 3D-QSAR methodology was tested on several sets of ligands for which the three-dimensional structure of the target protein has been solved - namely estrogen receptor, acetylcholine esterase and protein-tyrosine-phosphatase 1B. The molecular alignments of the studied ligands were determined using the docking program AutoDock and were compared with the X-ray structures of the corresponding protein-ligand complexes. The automatically generated protein-based ligand alignment obtained was subsequently taken as basis for a comparative field analysis applying the GRID/GOLPE approach. Using GRID interaction fields and applying variable selection procedures, highly predictive models were obtained. It is expected that concepts from receptor-based 3D QSAR will be valuable tools for the analysis of high-throughput screening as well as virtual screening data

  16. 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.

  17. 3D-QSAR (CoMFA and CoMSIA) and pharmacophore (GALAHAD) studies on the differential inhibition of aldose reductase by flavonoid compounds.

    PubMed

    Caballero, Julio

    2010-11-01

    Inhibitory activities of flavonoid derivatives against aldose reductase (AR) enzyme were modelled by using CoMFA, CoMSIA and GALAHAD methods. CoMFA and CoMSIA methods were used for deriving quantitative structure-activity relationship (QSAR) models. All QSAR models were trained with 55 compounds, after which they were evaluated for predictive ability with additional 14 compounds. The best CoMFA model included both steric and electrostatic fields, meanwhile, the best CoMSIA model included steric, hydrophobic and H-bond acceptor fields. These models had a good predictive quality according to both internal and external validation criteria. On the other hand, GALAHAD was used for deriving a 3D pharmacophore model. Twelve active compounds were used for deriving this model. The obtained model included hydrophobe, hydrogen bond acceptor and hydrogen bond donor features; it was able to identify the active AR inhibitors from the remaining compounds. These in silico tools might be useful in the rational design of new AR inhibitors.

  18. Synthesis, biological evaluation and 3D-QSAR studies of novel 4,5-dihydro-1H-pyrazole niacinamide derivatives as BRAF inhibitors.

    PubMed

    Li, Cui-Yun; Li, Qing-Shan; Yan, Li; Sun, Xiao-Guang; Wei, Ran; Gong, Hai-Bin; Zhu, Hai-Liang

    2012-06-15

    A series of novel 4,5-dihydropyrazole derivatives containing niacinamide moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Results of the bioassays against BRAF(V600E) and WM266.4 human melanoma cell line showed several compounds to be endowed potent activities with IC(50) and GI(50) value in low micromolar range, among which compound 27e, (5-(4-Chlorophenyl)-3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)6-methylpyridin-3-yl methanone (IC(50)=0.20 μM, GI(50)=0.89 μM) was bearing the best bioactivity comparable with the positive control Sorafenib. Docking simulation was performed to determine the probable binding model and 3D-QSAR model was built to provide more pharmacophore understanding that could use to design new agents with more potent BRAF(V600E) inhibitory activity.

  19. 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.

  20. 2D- and 3D-QSAR studies of a series of benzopyranes and benzopyrano[3,4b][1,4]-oxazines as inhibitors of the multidrug transporter P-glycoprotein

    NASA Astrophysics Data System (ADS)

    Jabeen, Ishrat; Wetwitayaklung, Penpun; Chiba, Peter; Pastor, Manuel; Ecker, Gerhard F.

    2013-02-01

    The ATP-binding cassette efflux transporter P-glycoprotein (P-gp) is notorious for contributing to multidrug resistance in antitumor therapy. Due to its expression in many blood-organ barriers, it also influences the pharmacokinetics of drugs and drug candidates and is involved in drug/drug- and drug/nutrient interactions. However, due to lack of structural information the molecular basis of ligand/transporter interaction still needs to be elucidated. Towards this goal, a series of Benzopyranes and Benzopyrano[3,4b][1,4]oxazines have been synthesized and pharmacologically tested for their ability to inhibit P-gp mediated daunomycin efflux. Both quantitative structure-activity relationship (QSAR) models using simple physicochemical and novel GRID-independent molecular descriptors (GRIND) were established to shed light on the structural requirements for high P-gp inhibitory activity. The results from 2D-QSAR showed a linear correlation of vdW surface area (Å2) of hydrophobic atoms with the pharmacological activity. GRIND (3D-QSAR) studies allowed to identify important mutual distances between pharmacophoric features, which include one H-bond donor, two H-bond acceptors and two hydrophobic groups as well as their distances from different steric hot spots of the molecules. Activity of the compounds particularly increases with increase of the distance of an H-bond donor or a hydrophobic feature from a particular steric hot spot of the benzopyrane analogs.

  1. 3D-QSAR Studies on Thiazolidin-4-one S1P1 Receptor Agonists by CoMFA and CoMSIA

    PubMed Central

    Qian, Chuiwen; Zheng, Junxia; Xiao, Gaokeng; Guo, Jialiang; Yang, Zhaoqi; Huang, Li; Chao, Wei; Rao, Longyi; Sun, Pinghua

    2011-01-01

    Selective S1P1 receptor agonists have therapeutic potential to treat a variety of immune-mediated diseases. A series of 2-imino-thiazolidin-4-one derivatives displaying potent S1P1 receptor agonistic activity were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q2 value of 0.751 and an r2 value of 0.973, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic, hydrophobic and H-bond donor descriptors, predicted a q2 value of 0.739 and an r2 value of 0.923. The models were graphically interpreted using contour plots which gave more insight into the structural requirements for increasing the activity of a compound, providing a solid basis for future rational design of more active S1P1 receptor agonists. PMID:22072901

  2. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing triaryl pyrazoline derivatives as potential B-Raf inhibitors.

    PubMed

    Yang, Yu-Shun; Yang, Bing; Zou, Yan; Li, Guigen; Zhu, Hai-Liang

    2016-07-01

    A series of novel dioxin-containing triaryl pyrazoline derivatives C1-C20 have been synthesized. Their B-Raf inhibitory and anti-proliferation activities were evaluated. Compound C6 displayed the most potent biological activity against B-Raf(V600E) and WM266.4 human melanoma cell line with corresponding IC50 value of 0.04μM and GI50 value of 0.87μM, being comparable with the positive controls and more potent than our previous best compounds. Moreover, C6 was selective for B-Raf(V600E) from B-Raf(WT), C-Raf and EGFR and low toxic. The docking simulation suggested the potent bioactivity might be caused by breaking the limit of previous binding pattern. A new 3D QSAR model was built with the activity data and binding conformations to conduct visualized SAR discussion as well as to introduce new directions. Stretching the backbone to outer space or totally reversing the backbone are both potential orientations for future researches.

  3. Synthesis, antiviral activity, 3D-QSAR, and interaction mechanisms study of novel malonate derivatives containing quinazolin-4(3H)-one moiety.

    PubMed

    Chen, Meihang; Li, Pei; Hu, Deyu; Zeng, Song; Li, Tianxian; Jin, Linhong; Xue, Wei; Song, Baoan

    2016-01-01

    A series of novel malonate derivatives containing quinazolin-4(3H)-one moiety were synthesized and evaluated for their antiviral activities against cucumber mosaic virus (CMV). Results indicated that the title compounds exhibited good antiviral activities. Notably, compounds g15, g16, g17, and g18 exhibited excellent curative activities in vivo against CMV, with 50% effective concentration (EC50) values of 208.36, 153.78, 181.47, and 164.72μg/mL, respectively, which were better than that of Ningnanmycin (256.35μg/mL) and Ribavirin (523.34μg/mL). Moreover, statistically valid three-dimensional quantitative structure-activity relationship (3D-QSAR) models with good correlation and predictive power were obtained with comparative molecular field analysis (CoMFA) steric and electrostatic fields (r(2)=0.990, q(2)=0.577) and comparative molecular similarity indices analysis (CoMSIA) with combined steric, electrostatic, hydrophobic and hydrogen bond acceptor fields (r(2)=0.977, q(2)=0.516), respectively. Based on those models, compound g25 was designed, synthesized, and showed better curative activity (146.30μg/mL) than that of compound g16. The interaction of between cucumber mosaic virus coat protein (CMV CP) and g25 with 1:1.83 ratio is typically spontaneous and exothermic with micromole binding affinity by isothermal titration calorimetry (ITC) and fluorescence spectroscopy investigation.

  4. Antimycobacterial activity evaluation, time-kill kinetic and 3D-QSAR study of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives.

    PubMed

    Kumar, Deepak; Raj, K Kranthi; Bailey, MaiAnn; Alling, Torey; Parish, Tanya; Rawat, Diwan S

    2013-03-01

    A series of C-(3-aminomethyl-cyclohexyl)-methylamine derivatives were synthesized and evaluated for their antitubercular activity. Some of the compounds exhibited potent activity against Mycobacterium tuberculosis H37Rv. One of the compound having t-butyl at para position of the benzene ring showed excellent activity even better than the standard drug ethambutol with MIC value 1.1 ± 0.2 μM. The time-kill kinetics study of two most active compounds showed rapid killing of the M. tuberculosis within 4 days. Additionally atom-based quantitative structure-activity relationship (QSAR) model was developed that gave a statistically satisfying result (R(2))=0.92, Q(2)=0.75, Pearson-R=0.96 and effectively predicts the anti-tuberculosis activity of training and test set compounds.

  5. 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.

  6. Molecular modeling studies of [6,6,5] Tricyclic Fused Oxazolidinones as FXa inhibitors using 3D-QSAR, Topomer CoMFA, molecular docking and molecular dynamics simulations.

    PubMed

    Xu, Cheng; Ren, Yujie

    2015-10-15

    Coagulation factor Xa (Factor Xa, FXa) is a particularly promising target for novel anticoagulant therapy. The first oral factor Xa inhibitor has been approved in the EU and Canada in 2008. In this work, 38 [6,6,5] Tricyclic Fused Oxazolidinones were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics and Topomer CoMFA (comparative molecular field analysis) were used to build 3D-QSAR models. The results show that the best CoMFA model has q(2)=0.511 and r(2)=0.984, the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.700 and r(2)=0.993 and the Topomer CoMFA analysis has q(2)=0.377 and r(2)=0.886. The results indicated the steric, hydrophobic, H-acceptor and electrostatic fields play key roles in models. Molecular docking and molecular dynamics explored the binding relationship of the ligand and the receptor protein.

  7. Comparison of Different 2D and 3D-QSAR Methods on Activity Prediction of Histamine H3 Receptor Antagonists.

    PubMed

    Dastmalchi, Siavoush; Hamzeh-Mivehroud, Maryam; Asadpour-Zeynali, Karim

    2012-01-01

    Histamine H3 receptor subtype has been the target of several recent drug development programs. Quantitative structure-activity relationship (QSAR) methods are used to predict the pharmaceutically relevant properties of drug candidates whenever it is applicable. The aim of this study was to compare the predictive powers of three different QSAR techniques, namely, multiple linear regression (MLR), artificial neural network (ANN), and HASL as a 3D QSAR method, in predicting the receptor binding affinities of arylbenzofuran histamine H3 receptor antagonists. Genetic algorithm coupled partial least square as well as stepwise multiple regression methods were used to select a number of calculated molecular descriptors to be used in MLR and ANN-based QSAR studies. Using the leave-group-out cross-validation technique, the performances of the MLR and ANN methods were evaluated. The calculated values for the mean absolute percentage error (MAPE), ranging from 2.9 to 3.6, and standard deviation of error of prediction (SDEP), ranging from 0.31 to 0.36, for both MLR and ANN methods were statistically comparable, indicating that both methods perform equally well in predicting the binding affinities of the studied compounds toward the H3 receptors. On the other hand, the results from 3D-QSAR studies using HASL method were not as good as those obtained by 2D methods. It can be concluded that simple traditional approaches such as MLR method can be as reliable as those of more advanced and sophisticated methods like ANN and 3D-QSAR analyses.

  8. Pharmacophore modeling, comprehensive 3D-QSAR, and binding mode analysis of TGR5 agonists.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2017-04-01

    Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. Pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. The generated best six featured pharmacophore model AAHHRR consists of two hydrogen bond acceptors (A): two hydrophobic groups (H) and two aromatic rings (R). The constructed 3D-QSAR model acquired excellent correlation coefficient value (R(2 )=( )0.9018), exhibited good predictive power (Q(2 )=( )0.8494) and high Fisher ratio (F = 61.2). The pharmacophore model was validated through Guner-Henry (GH) scoring method. The GH value of 0.5743 indicated that the AAHHRR model was statistically valuable and reliable in the identification of TGR5 agonists. Furthermore, the combined approach of molecular docking and binding free energy calculations were carried out for the 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides to explore the binding mode and interaction pattern. The generated contour maps revealed the important structural insights for the activity of the compounds. The results obtained from this study could be helpful in the development of novel and more potent agonists of TGR5.

  9. Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors

    PubMed Central

    Zhou, Nannan; Xu, Yuan; Liu, Xian; Wang, Yulan; Peng, Jianlong; Luo, Xiaomin; Zheng, Mingyue; Chen, Kaixian; Jiang, Hualiang

    2015-01-01

    The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR) model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC50 units from measured inhibition affinities and a Pearson’s correlation coefficient R2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor). Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors. PMID:26110383

  10. 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.

  11. 3D QSAR studies, pharmacophore modeling, and virtual screening of diarylpyrazole-benzenesulfonamide derivatives as a template to obtain new inhibitors, using human carbonic anhydrase II as a model protein.

    PubMed

    Entezari Heravi, Yeganeh; Sereshti, Hassan; Saboury, Ali Akbar; Ghasemi, Jahan; Amirmostofian, Marzieh; Supuran, Claudiu T

    2017-12-01

    A 3D-QSAR modeling was performed on a series of diarylpyrazole-benzenesulfonamide derivatives acting as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The compounds were collected from two datasets with the same scaffold, and utilized as a template for a new pharmacophore model to screen the ZINC database of commercially available derivatives. The datasets were divided into training, test, and validation sets. As the first step, comparative molecular field analysis (CoMFA), CoMFA region focusing and comparative molecular similarity indices analysis (CoMSIA) in parallel with docking studies were applied to a set of 41 human (h) CA II inhibitors. The validity and the prediction capacity of the resulting models were evaluated by leave-one-out (LOO) cross-validation approach. The reliability of the model for the prediction of possibly new CA inhibitors was also tested.

  12. Alignment-independent technique for 3D QSAR analysis.

    PubMed

    Wilkes, Jon G; Stoyanova-Slavova, Iva B; Buzatu, Dan A

    2016-04-01

    Molecular biochemistry is controlled by 3D phenomena but structure-activity models based on 3D descriptors are infrequently used for large data sets because of the computational overhead for determining molecular conformations. A diverse dataset of 146 androgen receptor binders was used to investigate how different methods for defining molecular conformations affect the performance of 3D-quantitative spectral data activity relationship models. Molecular conformations tested: (1) global minimum of molecules' potential energy surface; (2) alignment-to-templates using equal electronic and steric force field contributions; (3) alignment using contributions "Best-for-Each" template; (4) non-energy optimized, non-aligned (2D > 3D). Aggregate predictions from models were compared. Highest average coefficients of determination ranged from R Test (2) = 0.56 to 0.61. The best model using 2D > 3D (imported directly from ChemSpider) produced R Test (2) = 0.61. It was superior to energy-minimized and conformation-aligned models and was achieved in only 3-7 % of the time required using the other conformation strategies. Predictions averaged from models built on different conformations achieved a consensus R Test (2) = 0.65. The best 2D > 3D model was analyzed for underlying structure-activity relationships. For the compound strongest binding to the androgen receptor, 10 substructural features contributing to binding were flagged. Utility of 2D > 3D was compared for two other activity endpoints, each modeling a medium sized data set. Results suggested that large scale, accurate predictions using 2D > 3D SDAR descriptors may be produced for interactions involving endocrine system nuclear receptors and other data sets in which strongest activities are produced by fairly inflexible substrates.

  13. Alignment-independent technique for 3D QSAR analysis

    NASA Astrophysics Data System (ADS)

    Wilkes, Jon G.; Stoyanova-Slavova, Iva B.; Buzatu, Dan A.

    2016-04-01

    Molecular biochemistry is controlled by 3D phenomena but structure-activity models based on 3D descriptors are infrequently used for large data sets because of the computational overhead for determining molecular conformations. A diverse dataset of 146 androgen receptor binders was used to investigate how different methods for defining molecular conformations affect the performance of 3D-quantitative spectral data activity relationship models. Molecular conformations tested: (1) global minimum of molecules' potential energy surface; (2) alignment-to-templates using equal electronic and steric force field contributions; (3) alignment using contributions "Best-for-Each" template; (4) non-energy optimized, non-aligned (2D > 3D). Aggregate predictions from models were compared. Highest average coefficients of determination ranged from R Test 2 = 0.56 to 0.61. The best model using 2D > 3D (imported directly from ChemSpider) produced R Test 2 = 0.61. It was superior to energy-minimized and conformation-aligned models and was achieved in only 3-7 % of the time required using the other conformation strategies. Predictions averaged from models built on different conformations achieved a consensus R Test 2 = 0.65. The best 2D > 3D model was analyzed for underlying structure-activity relationships. For the compound strongest binding to the androgen receptor, 10 substructural features contributing to binding were flagged. Utility of 2D > 3D was compared for two other activity endpoints, each modeling a medium sized data set. Results suggested that large scale, accurate predictions using 2D > 3D SDAR descriptors may be produced for interactions involving endocrine system nuclear receptors and other data sets in which strongest activities are produced by fairly inflexible substrates.

  14. Combined 3D-QSAR, Molecular Docking and Molecular Dynamics Study on Derivatives of Peptide Epoxyketone and Tyropeptin-Boronic Acid as Inhibitors Against the β5 Subunit of Human 20S Proteasome

    PubMed Central

    Liu, Jianling; Zhang, Hong; Xiao, Zhengtao; Wang, Fangfang; Wang, Xia; Wang, Yonghua

    2011-01-01

    An abnormal ubiquitin-proteasome is found in many human diseases, especially in cancer, and has received extensive attention as a promising therapeutic target in recent years. In this work, several in silico models have been built with two classes of proteasome inhibitors (PIs) by using 3D-QSAR, homology modeling, molecular docking and molecular dynamics (MD) simulations. The study resulted in two types of satisfactory 3D-QSAR models, i.e., the CoMFA model (Q2 = 0.462, R2pred = 0.820) for epoxyketone inhibitors (EPK) and the CoMSIA model (Q2 = 0.622, R2pred = 0.821) for tyropeptin-boronic acid derivatives (TBA). From the contour maps, some key structural factors responsible for the activity of these two series of PIs are revealed. For EPK inhibitors, the N-cap part should have higher electropositivity; a large substituent such as a benzene ring is favored at the C6-position. In terms of TBA inhibitors, hydrophobic substituents with a larger size anisole group are preferential at the C8-position; higher electropositive substituents like a naphthalene group at the C3-position can enhance the activity of the drug by providing hydrogen bond interaction with the protein target. Molecular docking disclosed that residues Thr60, Thr80, Gly106 and Ser189 play a pivotal role in maintaining the drug-target interactions, which are consistent with the contour maps. MD simulations further indicated that the binding modes of each conformation derived from docking is stable and in accord with the corresponding structure extracted from MD simulation overall. These results can offer useful theoretical references for designing more potent PIs. PMID:21673924

  15. 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

  16. Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors

    NASA Astrophysics Data System (ADS)

    Sippl, Wolfgang; Contreras, Jean-Marie; Parrot, Isabelle; Rival, Yveline M.; Wermuth, Camille G.

    2001-05-01

    The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q2 LOO=0.937, q2 L50% O=0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model.

  17. Inhibitory mode of indole-2-carboxamide derivatives against HLGPa: molecular docking and 3D-QSAR analyses.

    PubMed

    Liu, Guixia; Zhang, Zhenshan; Luo, Xiaomin; Shen, Jianhua; Liu, Hong; Shen, Xu; Chen, Kaixian; Jiang, Hualiang

    2004-08-01

    The interaction of a series of indole-2-carboxamide compounds with human liver glycogen phosphorylase a (HLGPa) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0 was employed to locate the binding orientations and conformations of the inhibitors interacting with HLGPa. The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The very similar binding conformations of these inhibitors show that they interact with HLGPa in a very similar way. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. The structural and energetic differences in inhibitory potencies of indole-2-carboxamide compounds were reasonably explored. Using the binding conformations of indole-2-carboxamides, consistent and highly predictive 3D-QSAR models were developed by CoMFA and CoMSIA analyses. The q2 values are 0.697 and 0.622 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four compounds that were not included in the training set. Mapping these models back to the topology of the active site of HLGPa leads to a better understanding of the vital indole-2-carboxamide-HLGPa interactions. Structure-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel inhibitor design.

  18. Docking and 3-D QSAR studies on indolyl aryl sulfones. Binding mode exploration at the HIV-1 reverse transcriptase non-nucleoside binding site and design of highly active N-(2-hydroxyethyl)carboxamide and N-(2-hydroxyethyl)carbohydrazide derivatives.

    PubMed

    Ragno, Rino; Artico, Marino; De Martino, Gabriella; La Regina, Giuseppe; Coluccia, Antonio; Di Pasquali, Alessandra; Silvestri, Romano

    2005-01-13

    Three-dimensional quantitative structure-activity relationship (3-D QSAR) studies and docking simulations were developed on indolyl aryl sulfones (IASs), a class of novel HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (Silvestri, et al. J. Med. Chem. 2003, 46, 2482-2493) highly active against wild type and some clinically relevant resistant strains (Y181C, the double mutant K103N-Y181C, and the K103R-V179D-P225H strain, highly resistant to efavirenz). Predictive 3-D QSAR models using the combination of GRID and GOLPE programs were obtained using a receptor-based alignment by means of docking IASs into the non-nucleoside binding site (NNBS) of RT. The derived 3-D QSAR models showed conventional correlation (r(2)) and cross-validated (q(2)) coefficients values ranging from 0.79 to 0.93 and from 0.59 to 0.84, respectively. All described models were validated by an external test set compiled from previously reported pyrryl aryl sulfones (Artico, et al. J. Med. Chem. 1996, 39, 522-530). The most predictive 3-D QSAR model was then used to predict the activity of novel untested IASs. The synthesis of six designed derivatives (prediction set) allowed disclosure of new IASs endowed with high anti-HIV-1 activities.

  19. 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

  20. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors.

    PubMed

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-06-08

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.

  1. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors

    NASA Astrophysics Data System (ADS)

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-06-01

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.

  2. Application of 3D-QSAR techniques in anti-HIV-1 drug design--an overview.

    PubMed

    Debnath, Asim Kumar

    2005-01-01

    Despite the availability of several classes of drugs against acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus type 1(HIV-1), this deadly disease showing very little sign of containment, especially in Sub-Saharan Africa and South-East Asia. More than 20 million people died since the first diagnosis of AIDS more than twenty years ago and almost 40 million people are currently living with HIV/AIDS. Structure-based drug design effort was immensely successful in identifying several drugs that are currently available for the treatment of HIV-1. Many applications have been reported on the use of quantitative structure-activity relationship (QSAR) studies to understand the drug-receptor interactions and help in the design of more effective analogs. Extensive application was also reported on the application of 3D-QSAR techniques, such as, Comparative Molecular Field Analysis (CoMFA), Comparative Molecular Similarity Analysis (CoMSIA), pharmacophore generation using Catalyst/HypoGen, free-energy binding analysis, GRID/GOLPE, HINT-based techniques, etc. in anti-HIV-1 drug discovery programs in academia and industry. We have attempted to put together a comprehensive overview on the 3D-QSAR applications in anti-HIV-1 drug design reported in the literature during the last decade.

  3. The 3-D QSAR study of anticancer 1-N-substituted imidazo- and pyrrolo-quinoline-4,9-dione derivatives by CoMFA and CoMSIA.

    PubMed

    Suh, M E; Kang, M J; Park, S Y

    2001-11-01

    The 3-D QSAR analysis with new imidazo- and pyrrolo-quinolinedione derivatives was conducted by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). When crossvalidation value (q(2)) is 0.844 at four components, the Pearson correlation coefficient (r(2)) of the CoMFA is 0.964. In the CoMSIA, q(2) is 0.709 at six components and r(2) is 0.969. Unknown samples were analyzed, using QSAR analyzed results from the CoMFA and CoMSIA methods. Excellent agreement was obtained between, with an error range of 0.01-0.15 the calculated values and measured in vitro cytotoxic activities against human lung A-549 cancer cell lines.

  4. Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors

    PubMed Central

    Yang, Bing; Yang, Yu-Shun; Yang, Na; Li, Guigen; Zhu, Hai-Liang

    2016-01-01

    A series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future. PMID:27273260

  5. 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.

  6. 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.

  7. 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.

  8. Novel TOPP descriptors in 3D-QSAR analysis of apoptosis inducing 4-aryl-4H-chromenes: comparison versus other 2D- and 3D-descriptors.

    PubMed

    Sciabola, Simone; Carosati, Emanuele; Cucurull-Sanchez, Lourdes; Baroni, Massimo; Mannhold, Raimund

    2007-10-01

    Novel 3D-descriptors using Triplets Of Pharmacophoric Points (TOPP) were evaluated in QSAR-studies on 80 apoptosis-inducing 4-aryl-4H-chromenes. A predictive QSAR model was obtained using PLS, confirmed by means of internal and external validations. Performance of the TOPP approach was compared with that of other 2D- and 3D-descriptors; statistical analysis indicates that TOPP descriptors perform best. A ranking of TOPP>GRIND>BCI 4096=ECFP>FCFP>GRID-GOLPE>DRAGON>MDL 166 was achieved. Finally, in a 'consensus' analysis predictions obtained using the single methods were compared with an average approach using six out of eight methods. The use of the average is statistically superior to the single methods. Beyond it, the use of several methods can help to easily investigate the presence/absence of outliers according to the 'consensus' of the predicted values: agreement among all the methods indicates a precise prediction, whereas large differences between predicted values (for the same compounds by different methods) would demand caution when using such predictions.

  9. 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.

  10. Generation of pharmacophore and atom based 3D-QSAR model of novel isoquinolin-1-one and quinazolin-4-one-type inhibitors of TNFα.

    PubMed

    Hanumanthappa, Pradeep; Teli, Mahesh K; Krishnamurthy, Rajanikant G

    2012-05-01

    In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2=0.9965, Q2=0.6185, Root Mean Squared Error=0.4284 and Pearson-R=0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.

  11. Genotoxicity of quinolones: substituents contribution and transformation products QSAR evaluation using 2D and 3D models.

    PubMed

    Li, Min; Wei, Dongbin; Zhao, Huimin; Du, Yuguo

    2014-01-01

    The genotoxicity of 21 quinolones antibiotics was determined using SOS/umu assay. Some quinolones exhibited high genotoxicity, and the chemical substituent on quinolone ring significantly affected genotoxicity. To establish the relationship between genotoxicity and substituent, a 2D-QSAR model based on quantum chemical parameters was developed. Calculation suggested that both steric and electrostatic properties were correlated well with genotoxicity. Furthermore, the specific effect on three key active sites (1-, 7- and 8-positions) of quinolone ring was investigated using a 3D-QSAR (comparative molecular field analysis, CoMFA) method. From our modeling, the genotoxicity increased when substituents had: (1) big volume and/or positive charge at 1-position; (2) negative charge at 7-position; and (3) small volume and/or negative charge at 8-position. The developed QSAR models were applicable to estimate genotoxicity of quinolones antibiotics and their transformation products. It is noted that some of the transformation products exhibited higher genotoxicity comparing to their precursor (e.g., ciprofloxacin). This study provided an alternative way to understand the molecule genotoxicity of quinolones derivatives, as well as to evaluate their potential environmental risks.

  12. 3D QSAR models built on structure-based alignments of Abl tyrosine kinase inhibitors.

    PubMed

    Falchi, Federico; Manetti, Fabrizio; Carraro, Fabio; Naldini, Antonella; Maga, Giovanni; Crespan, Emmanuele; Schenone, Silvia; Bruno, Olga; Brullo, Chiara; Botta, Maurizio

    2009-06-01

    Quality QSAR: A combination of docking calculations and a statistical approach toward Abl inhibitors resulted in a 3D QSAR model, the analysis of which led to the identification of ligand portions important for affinity. New compounds designed on the basis of the model were found to have very good affinity for the target, providing further validation of the model itself.The X-ray crystallographic coordinates of the Abl tyrosine kinase domain in its active, inactive, and Src-like inactive conformations were used as targets to simulate the binding mode of a large series of pyrazolo[3,4-d]pyrimidines (known Abl inhibitors) by means of GOLD software. Receptor-based alignments provided by molecular docking calculations were submitted to a GRID-GOLPE protocol to generate 3D QSAR models. Analysis of the results showed that the models based on the inactive and Src-like inactive conformations had very poor statistical parameters, whereas the sole model based on the active conformation of Abl was characterized by significant internal and external predictive ability. Subsequent analysis of GOLPE PLS pseudo-coefficient contour plots of this model gave us a better understanding of the relationships between structure and affinity, providing suggestions for the next optimization process. On the basis of these results, new compounds were designed according to the hydrophobic and hydrogen bond donor and acceptor contours, and were found to have improved enzymatic and cellular activity with respect to parent compounds. Additional biological assays confirmed the important role of the selected compounds as inhibitors of cell proliferation in leukemia cells.

  13. Comprehensive 3D-QSAR and binding mode of BACE-1 inhibitors using R-group search and molecular docking.

    PubMed

    Huang, Dandan; Liu, Yonglan; Shi, Bozhi; Li, Yueting; Wang, Guixue; Liang, Guizhao

    2013-09-01

    The β-enzyme (BACE), which takes an active part in the processing of amyloid precursor protein, thereby leads to the production of amyloid-β (Aβ) in the brain, is a major therapeutic target against Alzheimer's disease. The present study is aimed at studying 3D-QSAR of BACE-1 inhibitors and their binding mode. We build a 3D-QSAR model involving 99 training BACE-1 inhibitors based on Topomer CoMFA, and 26 molecules are employed to validate the external predictive power of the model obtained. The multiple correlation coefficients of fitting modeling, leave one out cross validation, and external validation are 0.966, 0.767 and 0.784, respectively. Topomer search is used as a tool for virtual screening in lead-like compounds of ZINC databases (2012); as a result, we successfully design 30 new molecules with higher activity than that of all training and test inhibitors. Besides, Surflex-dock is employed to explore binding mode of the inhibitors studied when acting with BACE-1 enzyme. The result shows that the inhibitors closely interact with the key sites related to ASP93, THR133, GLN134, ASP289, GLY291, THR292, THR293, ASN294, ARG296 and SER386 of BACE-1.

  14. 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.

  15. Design, synthesis, and 3D QSAR of novel potent and selective aromatase inhibitors.

    PubMed

    Leonetti, Francesco; Favia, Angelo; Rao, Angela; Aliano, Rosaria; Paluszcak, Anja; Hartmann, Rolf W; Carotti, Angelo

    2004-12-30

    The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17-20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r(2) = 0.949, s = 0.216, and q(2) = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.

  16. Design, synthesis and 3D-QSAR of beta-carboline derivatives as potent antitumor agents.

    PubMed

    Cao, Rihui; Guan, Xiangdong; Shi, Buxi; Chen, Zhiyong; Ren, Zhenhua; Peng, Wenlie; Song, Huacan

    2010-06-01

    In a continuing effort to develop novel beta-carbolines endowed with better pharmacological profiles, a series of beta-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N2-benzylated beta-carbolinium bromides 56-60 represented the most potent compounds with IC50 values lower than 10 microM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA (q2=0.513, r2=0.862) and CoMSIA (q2=0.503, r2=0.831) models were developed for a set of 47 beta-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of beta-carboline ring.

  17. 3D-QSAR and molecular modeling of HIV-1 integrase inhibitors

    NASA Astrophysics Data System (ADS)

    Makhija, Mahindra T.; Kulkarni, Vithal M.

    2002-03-01

    Three-dimensional quantitative structure-activity relationship (3D QSAR) methods were applied on a series of inhibitors of HIV-1 integrase with respect to their inhibition of 3'-processing and 3'-end joining steps in vitro.The training set consisted of 27 compounds belonging to the class of thiazolothiazepines. The predictive ability of each model was evaluated using test set I consisting of four thiazolothiazepines and test set II comprised of seven compounds belonging to an entirely different structural class of coumarins. Maximum Common Substructure (MCS) based method was used to align the molecules and this was compared with other known methods of alignment. Two methods of 3D QSAR: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were analyzed in terms of their predictive abilities. CoMSIA produced significantly better results for all correlations. The results indicate a strong correlation between the inhibitory activity of these compounds and the steric and electrostatic fields around them. CoMSIA models with considerable internal as well as external predictive ability were obtained. A poor correlation obtained with hydrophobic field indicates that the binding of thiazolothiazepines to HIV-1 integrase is mainly enthalpic in nature. Further the most active compound of the series was docked into the active site using the crystal structure of integrase. The binding site was formed by the amino acid residues 64-67, 116, 148, 151-152, 155-156, and 159. The comparison of coefficient contour maps with the steric and electrostatic properties of the receptor shows high level of compatibility.

  18. Aldose reductase inhibitors for diabetic complications: Receptor induced atom-based 3D-QSAR analysis, synthesis and biological evaluation.

    PubMed

    Vyas, Bhawna; Singh, Manjinder; Kaur, Maninder; Bahia, Malkeet Singh; Jaggi, Amteshwar Singh; Silakari, Om; Singh, Baldev

    2015-06-01

    Herein, atom-based 3D-QSAR analysis was performed using receptor-guided alignment of 46 flavonoid inhibitors of aldose reductase (ALR2) enzyme. 3D-QSAR models were generated in PHASE programme, and the best model corresponding to PLS factor four (QSAR4), was selected based on different statistical parameters (i.e., Rtrain(2), 0.96; Qtest(2) 0.81; SD, 0.26). The contour plots of different structural properties generated from the selected model were utilized for the designing of five new congener molecules. These designed molecules were duly synthesized, and evaluated for their in vitro ALR2 inhibitory activity that resulted in the micromolar (IC50<22μM) activity of all molecules. Thus, the newly designed molecules having ALR inhibitory potential could be employed for the management of diabetic complications.

  19. Molecular docking and 3D-QSAR study on 4-(1H-indazol-4-yl) phenylamino and aminopyrazolopyridine urea derivatives as kinase insert domain receptor (KDR) inhibitors.

    PubMed

    Wu, Xiaoyun; Wu, Shuguang; Chen, Wen-Hua

    2012-03-01

    Vascular endothselial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2 or kinase insert domain receptor (KDR) have been identified as new promising targets for the design of novel anticancer agents. It is reported that 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives exhibit potent inhibitory activities toward KDR. To investigate how their chemical structures relate to the inhibitory activities and to identify the key structural elements that are required in the rational design of potential drug candidates of this class, molecular docking simulations and three-dimensional quantitative structure-activity relationship (3D-QSAR) methods were performed on 78 4-(1H-indazol-4-yl)phenylamino and aminopyrazolopyridine urea derivatives as KDR inhibitors. Surflex-dock was used to determine the probable binding conformations of all the compounds at the active site of KDR. As a result, multiple hydrophobic and hydrogen-bonding interactions were found to be two predominant factors that may be used to modulate the inhibitory activities. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models were developed based on the docking conformations. The CoMFA model produced statistically significant results with the cross-validated correlation coefficient q(2) of 0.504 and the non-cross-validated correlation coefficient r(2) of 0.913. The best CoMSIA model was obtained from the combination of steric, electrostatic and hydrophobic fields. Its q(2) and r(2) being 0.595 and 0.947, respectively, indicated that it had higher predictive ability than the CoMFA model. The predictive abilities of the two models were further validated by 14 test compounds, giving the predicted correction coefficients r (pred) (2) of 0.727 for CoMFA and 0.624 for CoMSIA, respectively. In addition, the CoMFA and CoMSIA models were used to guide the design of a series of new inhibitors of this class with

  20. Prediction and evaluation of the lipase inhibitory activities of tea polyphenols with 3D-QSAR models

    PubMed Central

    Li, Yi-Fang; Chang, Yi-Qun; Deng, Jie; Li, Wei-Xi; Jian, Jie; Gao, Jia-Suo; Wan, Xin; Gao, Hao; Kurihara, Hiroshi; Sun, Ping-Hua; He, Rong-Rong

    2016-01-01

    The extraordinary hypolipidemic effects of polyphenolic compounds from tea have been confirmed in our previous study. To gain compounds with more potent activities, using the conformations of the most active compound revealed by molecular docking, a 3D-QSAR pancreatic lipase inhibitor model with good predictive ability was established and validated by CoMFA and CoMISA methods. With good statistical significance in CoMFA (r2cv = 0.622, r2 = 0.956, F = 261.463, SEE = 0.096) and CoMISA (r2cv = 0.631, r2 = 0.932, F = 75.408, SEE = 0.212) model, we summarized the structure-activity relationship between polyphenolic compounds and pancreatic lipase inhibitory activities and find the bulky substituents in R2, R4 and R5, hydrophilic substituents in R1 and electron withdrawing groups in R2 are the key factors to enhance the lipase inhibitory activities. Under the guidance of the 3D-QSAR results, (2R,3R,2′R,3′R)-desgalloyloolongtheanin-3,3′-O-digallate (DOTD), a potent lipase inhibitor with an IC50 of 0.08 μg/ml, was obtained from EGCG oxidative polymerization catalyzed by crude polyphenol oxidase. Furthermore, DOTD was found to inhibit lipid absorption in olive oil-loaded rats, which was related with inhibiting the activities of lipase in the intestinal mucosa and contents. PMID:27694956

  1. The 3D-QSAR study of 110 diverse, dual binding, acetylcholinesterase inhibitors based on alignment independent descriptors (GRIND-2). The effects of conformation on predictive power and interpretability of the models.

    PubMed

    Vitorović-Todorović, Maja D; Cvijetić, Ilija N; Juranić, Ivan O; Drakulić, Branko J

    2012-09-01

    The 3D-QSAR analysis based on alignment independent descriptors (GRIND-2) was performed on the set of 110 structurally diverse, dual binding AChE reversible inhibitors. Three separate models were built, based on different conformations, generated following next criteria: (i) minimum energy conformations, (ii) conformation most similar to the co-crystalized ligand conformation, and (iii) docked conformation. We found that regardless on conformation used, all the three models had good statistic and predictivity. The models revealed the importance of protonated pyridine nitrogen of tacrine moiety for anti AChE activity, and recognized HBA and HBD interactions as highly important for the potency. This was revealed by the variables associated with protonated pyridinium nitrogen, and the two amino groups of the linker. MIFs calculated with the N1 (pyridinium nitrogen) and the DRY GRID probes in the AChE active site enabled us to establish the relationship between amino acid residues within AChE active site and the variables having high impact on models. External predictive power of the models was tested on the set of 40 AChE reversible inhibitors, most of them structurally different from the training set. Some of those compounds were tested on the different enzyme source. We found that external predictivity was highly sensitive on conformations used. Model based on docked conformations had superior predictive ability, emphasizing the need for the employment of conformations built by taking into account geometrical restrictions of AChE active site gorge.

  2. 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.

  3. 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.

  4. Market study: 3-D eyetracker

    NASA Technical Reports Server (NTRS)

    1977-01-01

    A market study of a proposed version of a 3-D eyetracker for initial use at NASA's Ames Research Center was made. The commercialization potential of a simplified, less expensive 3-D eyetracker was ascertained. Primary focus on present and potential users of eyetrackers, as well as present and potential manufacturers has provided an effective means of analyzing the prospects for commercialization.

  5. Design of the influenza virus inhibitors targeting the PA endonuclease using 3D-QSAR modeling, side-chain hopping, and docking.

    PubMed

    Yan, Zhihui; Zhang, Lijie; Fu, Haiyang; Wang, Zhonghua; Lin, Jianping

    2014-01-15

    With the emergence of drug resistance and the structural determination of the PA N-terminal domain (PAN), influenza endonucleases have become an attractive target for antiviral therapies for influenza infection. Here, we combined 3D-QSAR with side-chain hopping and molecular docking to produce novel structures as endonuclease inhibitors. First, a new molecular library was generated with side-chain hopping on an existing template molecule, L-742001, using an in-house fragment library that targets bivalent-cation-binding proteins. Then, the best 3D-QSAR model (AAAHR.500), with q(2)=0.76 and r(2)=0.97 from phase modeling, was constructed from 23 endonuclease inhibitors and validated with 17 test compounds. The AAAHR.500 model was then used to select effective candidates from the new molecular library. Combining 3D-QSAR with docking using Glide and Autodock, 13 compounds were considered the most likely candidate inhibitors. Docking studies showed that the binding modes of these compounds were consistent with the crystal structures of known inhibitors. These compounds could serve as potential endonuclease inhibitors for further biological activity tests.

  6. 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.

  7. Identification of potential influenza virus endonuclease inhibitors through virtual screening based on the 3D-QSAR model.

    PubMed

    Kim, J; Lee, C; Chong, Y

    2009-01-01

    Influenza endonucleases have appeared as an attractive target of antiviral therapy for influenza infection. With the purpose of designing a novel antiviral agent with enhanced biological activities against influenza endonuclease, a three-dimensional quantitative structure-activity relationships (3D-QSAR) model was generated based on 34 influenza endonuclease inhibitors. The comparative molecular similarity index analysis (CoMSIA) with a steric, electrostatic and hydrophobic (SEH) model showed the best correlative and predictive capability (q(2) = 0.763, r(2) = 0.969 and F = 174.785), which provided a pharmacophore composed of the electronegative moiety as well as the bulky hydrophobic group. The CoMSIA model was used as a pharmacophore query in the UNITY search of the ChemDiv compound library to give virtual active compounds. The 3D-QSAR model was then used to predict the activity of the selected compounds, which identified three compounds as the most likely inhibitor candidates.

  8. Inhibition of immune complex-mediated neutrophil oxidative metabolism: a pharmacophore model for 3-phenylcoumarin derivatives using GRIND-based 3D-QSAR and 2D-QSAR procedures.

    PubMed

    Kabeya, Luciana M; da Silva, Carlos H T P; Kanashiro, Alexandre; Campos, Joaquín M; Azzolini, Ana Elisa C S; Polizello, Ana Cristina M; Pupo, Mônica T; Lucisano-Valim, Yara M

    2008-05-01

    In this study, twenty hydroxylated and acetoxylated 3-phenylcoumarin derivatives were evaluated as inhibitors of immune complex-stimulated neutrophil oxidative metabolism and possible modulators of the inflammatory tissue damage found in type III hypersensitivity reactions. By using lucigenin- and luminol-enhanced chemiluminescence assays (CL-luc and CL-lum, respectively), we found that the 6,7-dihydroxylated and 6,7-diacetoxylated 3-phenylcoumarin derivatives were the most effective inhibitors. Different structural features of the other compounds determined CL-luc and/or CL-lum inhibition. The 2D-QSAR analysis suggested the importance of hydrophobic contributions to explain these effects. In addition, a statistically significant 3D-QSAR model built applying GRIND descriptors allowed us to propose a virtual receptor site considering pharmacophoric regions and mutual distances. Furthermore, the 3-phenylcoumarins studied were not toxic to neutrophils under the assessed conditions.

  9. 3D-QSAR analysis of a series of S-DABO derivatives as anti-HIV agents by CoMFA and CoMSIA.

    PubMed

    Xu, H R; Fu, L; Zhan, P; Liu, X Y

    2016-12-01

    In this study, we retrieved a series of 59 dihydroalkylthio-benzyloxopyrimidine (S-DABO) derivatives, which is a class of highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) reported from published articles, and analysed them with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Statistically significant three-dimensional quantitative structure-activity relationship (3D-QSAR) models by CoMFA and CoMSIA were derived from a training set of 46 compounds on the basis of the rigid body alignment. Further, the predictive ability of the QSAR models was validated by a test set of 13 compounds. Based on the information derived from CoMFA and CoMSIA contour maps, we have identified some steric and electrostatic features for improving the activities of these inhibitors, and we validated the 3D-QSAR results by a molecular docking method. On the basis of the obtained results, we designed a new series of S-DABO derivatives with high activities. Therefore, this study could be utilized to design more potent S-DABO analogues as anti-HIV agents.

  10. Pharmacophore generation and atom-based 3D-QSAR of novel quinoline-3-carbonitrile derivatives as Tpl2 kinase inhibitors.

    PubMed

    Teli, Mahesh Kumar; Rajanikant, G K

    2012-08-01

    Tumour progression locus-2 (Tpl2) is a serine/threonine kinase, which regulates the expression of tumour necrosis factor α. The article describes the development of a robust pharmacophore model and the investigation of structure-activity relationship analysis of quinoline-3-carbonitrile derivatives reported for Tpl2 kinase inhibition. A five point pharmacophore model (ADRRR) was developed and used to derive a predictive atom-based 3-dimensional quantitative structure activity relationship (3D-QSAR) model. The obtained 3D-QSAR model has an excellent correlation coefficient value (r(2)= 0.96), Fisher ratio (F = 131.9) and exhibited good predictive power (q(2) = 0.79). The QSAR model suggests that the inclusion of hydrophobic substituents will enhance the Tpl2 kinase inhibition. In addition, H-bond donating groups, negative ionic groups and electron withdrawing groups positively contribute to the Tpl2 kinase inhibition. Further, pharmacophoric model was validated by the receiver operating characteristic curve analysis and was employed for virtual screening to identify six potential Tpl2 kinase inhibitors. The findings of this study provide a set of guidelines for designing compounds with better Tpl2 kinase inhibitory potency.

  11. Local indices for similarity analysis (LISA)-a 3D-QSAR formalism based on local molecular similarity.

    PubMed

    Verma, Jitender; Malde, Alpeshkumar; Khedkar, Santosh; Iyer, Radhakrishnan; Coutinho, Evans

    2009-12-01

    A simple quantitative structure activity relationship (QSAR) approach termed local indices for similarity analysis (LISA) has been developed. In this technique, the global molecular similarity is broken up as local similarity at each grid point surrounding the molecules and is used as a QSAR descriptor. In this way, a view of the molecular sites permitting favorable and rational changes to enhance activity is obtained. The local similarity index, calculated on the basis of Petke's formula, segregates the regions into "equivalent", "favored similar", and "disfavored similar" (alternatively "favored dissimilar") potentials with respect to a reference molecule in the data set. The method has been tested on three large and diverse data sets-thrombin, glycogen phosphorylase b, and thermolysin inhibitors. The QSAR models derived using genetic algorithm incorporated partial least square analysis statistics are found to be comparable to the ones obtained by the standard three-dimensional (3D)-QSAR methods, such as comparative molecular field analysis and comparative molecular similarity indices analysis. The graphical interpretation of the LISA models is straightforward, and the outcome of the models corroborates well with literature data. The LISA models give insight into the binding mechanisms of the ligand with the enzyme and allow fine-tuning of the molecules at the local level to improve their activity.

  12. Development of 3D-QSAR Model for Acetylcholinesterase Inhibitors Using a Combination of Fingerprint, Molecular Docking, and Structure-Based Pharmacophore Approaches.

    PubMed

    Lee, Sehan; Barron, Mace G

    2015-11-01

    Acetylcholinesterase (AChE), a serine hydrolase vital for regulating the neurotransmitter acetylcholine in animals, has been used as a target for drugs and pesticides. With the increasing availability of AChE crystal structures, with or without ligands bound, structure-based approaches have been successfully applied to AChE inhibitors (AChEIs). The major limitation of these approaches has been the small applicability domain due to the lack of structural diversity in the training set. In this study, we developed a 3 dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitory activity of 89 reversible and irreversible AChEIs including drugs and insecticides. A 3D-fingerprint descriptor encoding protein-ligand interactions was developed using molecular docking and structure-based pharmacophore to rationalize the structural requirements responsible for the activity of these compounds. The obtained 3D-QSAR model exhibited high correlation value (R(2) = 0.93) and low mean absolute error (MAE = 0.32 log units) for the training set (n = 63). The model was predictive across a range of structures as shown by the leave-one-out cross-validated correlation coefficient (Q(2) = 0.89) and external validation results (n = 26, R(2) = 0.89, and MAE = 0.38 log units). The model revealed that the compounds with high inhibition potency had proper conformation in the active site gorge and interacted with key amino acid residues, in particular Trp84 and Phe330 at the catalytic anionic site, Trp279 at the peripheral anionic site, and Gly118, Gly119, and Ala201 at the oxyanion hole. The resulting universal 3D-QSAR model provides insight into the multiple molecular interactions determining AChEI potency that may guide future chemical design and regulation of toxic AChEIs.

  13. 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.

  14. Exploration of Novel Inhibitors for Bruton’s Tyrosine Kinase by 3D QSAR Modeling and Molecular Dynamics Simulation

    PubMed Central

    Choi, Light; Woo Lee, Keun

    2016-01-01

    Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in many cellular signaling pathways. B cell malignancies are dependent on BCR signaling, thus making BTK an efficient therapeutic target. Over the last few years, significant efforts have been made in order to develop BTK inhibitors to treat B-cell malignancies, and autoimmunity or allergy/hypersensitivity but limited success has been achieved. Here in this study, 3D QSAR pharmacophore models were generated for Btk based on known IC50 values and experimental energy scores with extensive validations. The five features pharmacophore model, Hypo1, includes one hydrogen bond acceptor lipid, one hydrogen bond donor, and three hydrophobic features, which has the highest correlation coefficient (0.98), cost difference (112.87), and low RMS (1.68). It was further validated by the Fisher’s randomization method and test set. The well validated Hypo1 was used as a 3D query to search novel Btk inhibitors with different chemical scaffold using high throughput virtual screening technique. The screened compounds were further sorted by applying ADMET properties, Lipinski’s rule of five and molecular docking studies to refine the retrieved hits. Furthermore, molecular dynamic simulation was employed to study the stability of docked conformation and to investigate the binding interactions in detail. Several important hydrogen bonds with Btk were revealed, which includes the gatekeeper residues Glu475 and Met 477 at the hinge region. Overall, this study suggests that the proposed hits may be more effective inhibitors for cancer and autoimmune therapy. PMID:26784025

  15. CoMFA and CoMSIA 3D-QSAR analysis on hydroxamic acid derivatives as urease inhibitors.

    PubMed

    Ul-Haq, Zaheer-; Wadood, Abdul; Uddin, Reaz

    2009-02-01

    Urease (EC 3.5.1.5) serves as a virulence factor in pathogens that are responsible for the development of many diseases in humans and animals. Urease allows soil microorganisms to use urea as a source of nitrogen and aid in the rapid break down of urea-based fertilizers resulting in phytopathicity. It has been well established that hydroxamic acids are the potent inhibitors of urease activity. The 3D-QSAR studies on thirty five hydroxamic acid derivatives as known urease inhibitors were performed by Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods to determine the factors required for the activity of these compounds. The CoMFA model produced statistically significant results with cross-validated (q(2)) 0.532 and conventional (r(2)) correlation coefficients 0.969.The model indicated that the steric field (70.0%) has greater influence on hydroxamic acid inhibitors than the electrostatic field (30.0%). Furthermore, five different fields: steric, electrostatic, hydrophobic, H-bond donor and H-bond acceptor assumed to generate the CoMSIA model, which gave q(2) 0.665 and r(2) 0.976.This model showed that steric (43.0%), electrostatic (26.4%) and hydrophobic (20.3%) properties played a major role in urease inhibition. The analysis of CoMFA and CoMSIA contour maps provided insight into the possible modification of the hydroxamic acid derivatives for improved activity.

  16. 3D-QSAR Design of New Escitalopram Derivatives for the Treatment of Major Depressive Disorders

    PubMed Central

    Avram, Speranta; Buiu, Catalin; Duda-Seiman, Daniel M.; Duda-Seiman, Corina; Mihailescu, Dan

    2010-01-01

    Antidepressants are psychiatric agents used for the treatment of different types of depression being at present amongst the most commonly prescribed drug, while their effectiveness and adverse effects are the subject of many studies and competing claims. Having studied five QSAR models predicting the biological activities of 18 antidepressants, already approved for clinical treatment, in interaction with the serotonin transporter (SERT), we attempted to establish the membrane ions’ contributions (sodium, potassium, chlorine and calcium) supplied by donor/acceptor hydrogen bond character and electrostatic field to the antidepressant activity. Significant cross-validated correlation q2 (0.5–0.6) and the fitted correlation r2 (0.7–0.82) coefficients were obtained indicating that the models can predict the antidepressant activity of compounds. Moreover, considering the contribution of membrane ions (sodium, potassium and calcium) and hydrogen bond donor character, we have proposed a library of 24 new escitalopram structures, some of them probably with significantly improved antidepressant activity in comparison with the parent compound. PMID:21179345

  17. 3D-QSAR AND CONTOUR MAP ANALYSIS OF TARIQUIDAR ANALOGUES AS MULTIDRUG RESISTANCE PROTEIN-1 (MRP1) INHIBITORS

    PubMed Central

    Kakarla, Prathusha; Inupakutika, Madhuri; Devireddy, Amith R.; Gunda, Shravan Kumar; Willmon, Thomas Mark; Ranjana, KC; Shrestha, Ugina; Ranaweera, Indrika; Hernandez, Alberto J.; Barr, Sharla; Varela, Manuel F.

    2016-01-01

    One of the major obstacles to the successful chemotherapy towards several cancers is multidrug resistance of human cancer cells to anti-cancer drugs. An important contributor to multidrug resistance is the human multidrug resistance protein-1 transporter (MRP1), which is an efflux pump of the ABC (ATP binding cassette) superfamily. Thus, highly efficacious, third generation MRP1 inhibitors, like tariquidar analogues, are promising inhibitors of multidrug resistance and are under clinical trials. To maximize the efficacy of MRP1 inhibitors and to reduce systemic toxicity, it is important to limit the exposure of MRP1 inhibitors and anticancer drugs to normal tissues and to increase their co-localization with tumor cells. Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) associated with 3D-Quantitiative structure-activity relationship (3D-QSAR) studies were performed on a series of tariquidar analogues, as selective MDR modulators. Best predictability was obtained with CoMFA model r2(non-cross-validated square of correlation coefficient) = 0.968, F value = 151.768 with five components, standard error of estimate = 0.107 while the CoMSIA yielded r2 = 0.982, F value = 60.628 with six components, and standard error of estimate = 0.154. These results indicate that steric, electrostatic, hydrophobic (lipophilic), and hydrogen bond donor substituents play significant roles in multidrug resistance modulation of tariquidar analogues upon MRP1. The tariquidar analogue and MRP1 binding and stability data generated from CoMFA and CoMSIA based 3D–contour maps may further aid in study and design of tariquidar analogues as novel, potent and selective MDR modulator drug candidates. PMID:26913287

  18. Receptor-based modeling and 3D-QSAR for a quantitative production of the butyrylcholinesterase inhibitors based on genetic algorithm.

    PubMed

    Zaheer-ul, Haq; Uddin, Reaz; Yuan, Hongbin; Petukhov, Pavel A; Choudhary, M Iqbal; Madura, Jeffry D

    2008-05-01

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been constructed using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a series of structurally related steroidal alkaloids as butyrylcholinesterase (BuChE) inhibitors. Docking studies were employed to position the inhibitors into the BuChE active site to determine the most probable binding mode. The strategy was to explore multiple inhibitor conformations in producing a more reliable 3D-QSAR model. These multiple conformations were derived using the FlexS program. The conformation selection step for CoMFA was done by genetic algorithm. The genetic algorithm based CoMFA approach was found to be the best. Both CoMFA and CoMSIA yielded significant cross-validated q(2) values of 0.701 and 0.627 and the r(2) values of 0.979 and 0.982, respectively. These statistically significant models were validated by a test set of five compounds. Comparison of CoMFA and CoMSIA contour maps helped to identify structural requirements for the inhibitors and serves as a basis for the design of the next generation of the inhibitor analogues. The results demonstrate that the combination of ligand-based and receptor-based modeling with use of a genetic algorithm is a powerful approach to build 3D-QSAR models. These data can be used for the lead optimization process with respect to inhibition enhancement which is important for the drug discovery and development for Alzheimer's disease.

  19. 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

  20. Atomic softness-based QSAR study of testosterone

    NASA Astrophysics Data System (ADS)

    Srivastava, H. K.; Pasha, F. A.; Singh, P. P.

    Ionization potential of an atom in a molecule, electron affinity of an atom in a molecule, and quantum chemical descriptor atomic softness values En‡-based quantitative structure-activity relationship (QSAR) study of testosterone derivatives have been done with the help of PM3 calculations on WinMOPAC 7.21 software. The 3D modeling and geometry optimization of all the compounds have been done with the help of PCMODEL software. The biological activities of testosterone derivatives have been taken from literature. The predicted values of biological activity with the help of multiple linear regression (MLR) analysis is very close to observed biological activity. The cross-validation coefficient and correlation coefficient also indicate that the QSAR model is valuable. Regression analysis shows a very good relationship with biological activity and En‡ values. With the help of these values, prediction of the biological activity of any unknown compound is possible.

  1. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach

    PubMed Central

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2017-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r2) value of 0.6774, cross-validated correlation coefficient (q2) of 0.6157 and co-relation coefficient for external test set (pred_r2) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of −10.097 and −9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  2. Mechanistic Insights into the Binding of Class IIa HDAC Inhibitors toward Spinocerebellar Ataxia Type-2: A 3D-QSAR and Pharmacophore Modeling Approach.

    PubMed

    Sinha, Siddharth; Goyal, Sukriti; Somvanshi, Pallavi; Grover, Abhinav

    2016-01-01

    Spinocerebellar ataxia (SCA-2) type-2 is a rare neurological disorder among the nine polyglutamine disorders, mainly caused by polyQ (CAG) trinucleotide repeats expansion within gene coding ataxin-2 protein. The expanded trinucleotide repeats within the ataxin-2 protein sequesters transcriptional cofactors i.e., CREB-binding protein (CBP), Ataxin-2 binding protein 1 (A2BP1) leading to a state of hypo-acetylation and transcriptional repression. Histone de-acetylases inhibitors (HDACi) have been reported to restore transcriptional balance through inhibition of class IIa HDAC's, that leads to an increased acetylation and transcription as demonstrated through in-vivo studies on mouse models of Huntington's. In this study, 61 di-aryl cyclo-propanehydroxamic acid derivatives were used for developing three dimensional (3D) QSAR and pharmacophore models. These models were then employed for screening and selection of anti-ataxia compounds. The chosen QSAR model was observed to be statistically robust with correlation coefficient (r(2)) value of 0.6774, cross-validated correlation coefficient (q(2)) of 0.6157 and co-relation coefficient for external test set (pred_r(2)) of 0.7570. A high F-test value of 77.7093 signified the robustness of the model. Two potential drug leads ZINC 00608101 (SEI) and ZINC 00329110 (ACI) were selected after a coalesce procedure of pharmacophore based screening using the pharmacophore model ADDRR.20 and structural analysis using molecular docking and dynamics simulations. The pharmacophore and the 3D-QSAR model generated were further validated for their screening and prediction ability using the enrichment factor (EF), goodness of hit (GH), and receiver operating characteristics (ROC) curve analysis. The compounds SEI and ACI exhibited a docking score of -10.097 and -9.182 kcal/mol, respectively. An evaluation of binding conformation of ligand-bound protein complexes was performed with MD simulations for a time period of 30 ns along with free

  3. New ligands with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors. Synthesis, receptor binding, and 3D-QSAR modeling.

    PubMed

    Audouze, Karine; Nielsen, Elsebet Østergaard; Olsen, Gunnar M; Ahring, Philip; Jørgensen, Tino Dyhring; Peters, Dan; Liljefors, Tommy; Balle, Thomas

    2006-06-01

    A new series of piperazines, diazepanes, diazocanes, diazabicyclononanes, and diazabicyclodecanes with affinity for the alpha4beta2 subtype of nicotinic acetylcholine receptors were synthesized on the basis of results from a previous computational study. A predictive 3D-QSAR model was developed using the GRID/GOLPE approach (R2 = 0.94, Q2 = 0.83, SDEP = 0.34). The SAR was interpreted in terms of contour maps of the PLS coefficients and in terms of a homology model of the alpha4beta2 subtype of the nicotinic acetylcholine receptors. The results reveal that hydrogen bonding from both hydrogens on the protonated amine and from the pyridine nitrogen to a water molecule as well as van der Waals interactions between the substituent bearing the protonated amine and the receptor is of importance for ligand affinity. The combination of 3D-QSAR and homology modeling proved successful for the interpretation of structure-affinity relationships as well as the validation of the individual modeling approaches.

  4. QSAR study and VolSurf characterization of anti-HIV quinolone library

    NASA Astrophysics Data System (ADS)

    Filipponi, Enrica; Cruciani, Gabriele; Tabarrini, Oriana; Cecchetti, Violetta; Fravolini, Arnaldo

    2001-03-01

    Antiviral quinolones are promising compounds in the search for new therapeutically effective agents for the treatment of AIDS. To rationalize the SAR for this new interesting class of anti-HIV derivatives, we performed a 3D-QSAR study on a library of 101 6-fluoro and 6-desfluoroquinolones, taken either from the literature or synthesized by us. The chemometric procedure involved a fully semiempirical minimization of the molecular structures by the AMSOL program, which takes into account the solvatation effect, and their 3D characterization by the VolSurf/GRID program. The QSAR analysis, based on PCA and PLS methods, shows the key structural features responsible for the antiviral activity.

  5. Identification of the Structural Features of Guanine Derivatives as MGMT Inhibitors Using 3D-QSAR Modeling Combined with Molecular Docking.

    PubMed

    Sun, Guohui; Fan, Tengjiao; Zhang, Na; Ren, Ting; Zhao, Lijiao; Zhong, Rugang

    2016-06-23

    DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT), which plays an important role in inducing drug resistance against alkylating agents that modify the O⁶ position of guanine in DNA, is an attractive target for anti-tumor chemotherapy. A series of MGMT inhibitors have been synthesized over the past decades to improve the chemotherapeutic effects of O⁶-alkylating agents. In the present study, we performed a three-dimensional quantitative structure activity relationship (3D-QSAR) study on 97 guanine derivatives as MGMT inhibitors using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods. Three different alignment methods (ligand-based, DFT optimization-based and docking-based alignment) were employed to develop reliable 3D-QSAR models. Statistical parameters derived from the models using the above three alignment methods showed that the ligand-based CoMFA (Qcv² = 0.672 and Rncv² = 0.997) and CoMSIA (Qcv² = 0.703 and Rncv² = 0.946) models were better than the other two alignment methods-based CoMFA and CoMSIA models. The two ligand-based models were further confirmed by an external test-set validation and a Y-randomization examination. The ligand-based CoMFA model (Qext² = 0.691, Rpred² = 0.738 and slope k = 0.91) was observed with acceptable external test-set validation values rather than the CoMSIA model (Qext² = 0.307, Rpred² = 0.4 and slope k = 0.719). Docking studies were carried out to predict the binding modes of the inhibitors with MGMT. The results indicated that the obtained binding interactions were consistent with the 3D contour maps. Overall, the combined results of the 3D-QSAR and the docking obtained in this study provide an insight into the understanding of the interactions between guanine derivatives and MGMT protein, which will assist in designing novel MGMT inhibitors with desired activity.

  6. A class of novel Schiff's bases: Synthesis, therapeutic action for chronic pain, anti-inflammation and 3D QSAR analysis.

    PubMed

    Zhou, Yinjian; Zhao, Ming; Wu, Yingting; Li, Chunyu; Wu, Jianhui; Zheng, Meiqing; Peng, Li; Peng, Shiqi

    2010-03-15

    To discover analgesics for treating chronic pain 17 novel Schiff's bases, N,N'-(Z-allylidene-1,3-diyl)bisamino acid methyl esters were prepared from 1,1,3,3,-tetramethoxypropane and amino acid methyl esters. On tail-flick mouse model 20 micromol/kg of these Schiff's bases were orally administered, the analgesic action started 30 min after administration, reached the maximum 120 min after administration, and at 180 min this action was still observed. On a xylene-induced ear edema mouse model 20 micromol/kg of these Schiff's bases exhibited desirable anti-inflammation. Thus the present Schiff's bases are able to treat chronic pain from inflammation. The effect of the side chains of the amino acid residues of these Schiff's bases on the analgesic activity was explained with 3D QSAR.

  7. Elucidating the inhibiting mode of AHPBA derivatives against HIV-1 protease and building predictive 3D-QSAR models.

    PubMed

    Huang, Xaioqin; Xu, Liaosa; Luo, Xiaomin; Fan, Kangnian; Ji, Ruyun; Pei, Gang; Chen, Kaixian; Jiang, Hualiang

    2002-01-17

    The Lamarckian genetic algorithm of AutoDock 3.0 has been used to dock 27 3(S)-amino-2(S)-hydroxyl-4-phenylbutanoic acids (AHPBAs) into the active site of HIV-1 protease (HIVPR). The binding mode was demonstrated in the aspects of the inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters (tau(1), tau(2), and tau(3) listed in Table 2) and root mean square deviation values as compared with the known inhibitor, kni272,(28) show that both kinds of inhibitors interact with HIVPR in a very similar way. The r(2) value of 0.860 indicates that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of AHPBAs were reasonably explored. Using the binding conformations of AHPBAs, consistent and highly predictive 3D-QSAR models were developed by performing CoMFA, CoMSIA, and HQSAR analyses. The reasonable r(corss)(2) values were 0.613, 0.530, and 0.717 for CoMFA, CoMSIA, and HQSAR models, respectively. The predictive ability of these models was validated by kni272 and a set of nine compounds that were not included in the training set. Mapping these models back to the topology of the active site of HIVPR leads to a better understanding of vital AHPBA-HIVPR interactions. Structural-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel HIVPR inhibitors.

  8. Molecular modeling studies of 4,5-dihydro-1H-pyrazolo[4,3-h] quinazoline derivatives as potent CDK2/Cyclin a inhibitors using 3D-QSAR and docking.

    PubMed

    Ai, Yong; Wang, Shao-Teng; Sun, Ping-Hua; Song, Fa-Jun

    2010-09-28

    CDK2/cyclin A has appeared as an attractive drug targets over the years with diverse therapeutic potentials. A computational strategy based on comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) followed by molecular docking studies were performed on a series of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as potent CDK2/cyclin A inhibitors. The CoMFA and CoMSIA models, using 38 molecules in the training set, gave r(2) (cv) values of 0.747 and 0.518 and r(2) values of 0.970 and 0.934, respectively. 3D contour maps generated by the CoMFA and CoMSIA models were used to identify the key structural requirements responsible for the biological activity. Molecular docking was applied to explore the binding mode between the ligands and the receptor. The information obtained from molecular modeling studies may be helpful to design novel inhibitors of CDK2/cyclin A with desired activity.

  9. 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.

  10. Pharmacophore modelling, atom-based 3D-QSAR generation and virtual screening of molecules projected for mPGES-1 inhibitory activity.

    PubMed

    Misra, S; Saini, M; Ojha, H; Sharma, D; Sharma, K

    2017-01-01

    COX-2 inhibitors exhibit anticancer effects in various cancer models but due to the adverse side effects associated with these inhibitors, targeting molecules downstream of COX-2 (such as mPGES-1) has been suggested. Even after calls for mPGES-1 inhibitor design, to date there are only a few published inhibitors targeting the enzyme and displaying anticancer activity. In the present study, we have deployed both ligand and structure-based drug design approaches to hunt novel drug-like candidates as mPGES-1 inhibitors. Fifty-four compounds with tested mPGES-1 inhibitory value were used to develop a model with four pharmacophoric features. 3D-QSAR studies were undertaken to check the robustness of the model. Statistical parameters such as r(2) = 0.9924, q(2) = 0.5761 and F test = 1139.7 indicated significant predictive ability of the proposed model. Our QSAR model exhibits sites where a hydrogen bond donor, hydrophobic group and the aromatic ring can be substituted so as to enhance the efficacy of the inhibitor. Furthermore, we used our validated pharmacophore model as a three-dimensional query to screen the FDA-approved Lopac database. Finally, five compounds were selected as potent mPGES-1 inhibitors on the basis of their docking energy and pharmacokinetic properties such as ADME and Lipinski rule of five.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  12. Structure-based rational quest for potential novel inhibitors of human HMG-CoA reductase by combining CoMFA 3D QSAR modeling and virtual screening.

    PubMed

    Zhang, Qing Y; Wan, Jian; Xu, Xin; Yang, Guang F; Ren, Yan L; Liu, Jun J; Wang, Hui; Guo, Yu

    2007-01-01

    3-Hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) catalyzes the formation of mevalonate. In many classes of organisms, this is the committed step leading to the synthesis of essential compounds, such as cholesterol. However, a high level of cholesterol is an important risk factor for coronary heart disease, for which an effective clinical treatment is to block HMGR using inhibitors like statins. Recently the structures of catalytic portion of human HMGR complexed with six different statins have been determined by a delicate crystallography study (Istvan and Deisenhofer Science 2001, 292, 1160-1164), which established a solid basis of structure and mechanism for the rational design, optimization, and development of even better HMGR inhibitors. In this study, three-dimensional quantitative structure-activity relationship (3D QSAR) with comparative molecular field analysis (CoMFA) was performed on a training set of up to 35 statins and statin-like compounds. Predictive models were established by using two different ways: (1) Models-fit, obtained by SYBYL conventional fit-atom molecular alignment rule, has cross-validated coefficients (q2) up to 0.652 and regression coefficients (r2) up to 0.977. (2) Models-dock, obtained by FlexE by docking compounds into the HMGR active site, has cross-validated coefficients (q2) up to 0.731 and regression coefficients (r2) up to 0.947. These models were further validated by an external testing set of 12 statins and statin-like compounds. Integrated with CoMFA 3D QSAR predictive models, molecular surface property (electrostatic and steric) mapping and structure-based (both ligand and receptor) virtual screening have been employed to explore potential novel hits for the HMGR inhibitors. A representative set of eight new compounds of non-statin-like structures but with high pIC(50) values were sorted out in the present study.

  13. Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches

    NASA Astrophysics Data System (ADS)

    Ragno, Rino; Ballante, Flavio; Pirolli, Adele; Wickersham, Richard B.; Patsilinakos, Alexandros; Hesse, Stéphanie; Perspicace, Enrico; Kirsch, Gilbert

    2015-08-01

    Vascular endothelial growth factor receptor-2, (VEGFR-2), is a key element in angiogenesis, the process by which new blood vessels are formed, and is thus an important pharmaceutical target. Here, 3-D quantitative structure-activity relationship (3-D QSAR) were used to build a quantitative screening and pharmacophore model of the VEGFR-2 receptors for design of inhibitors with improved activities. Most of available experimental data information has been used as training set to derive optimized and fully cross-validated eight mono-probe and a multi-probe quantitative models. Notable is the use of 262 molecules, aligned following both structure-based and ligand-based protocols, as external test set confirming the 3-D QSAR models' predictive capability and their usefulness in design new VEGFR-2 inhibitors. From a survey on literature, this is the first generation of a wide-ranging computational medicinal chemistry application on VEGFR2 inhibitors.

  14. Pharmacophore generation, atom-based 3D-QSAR, HQSAR and activity cliff analyses of benzothiazine and deazaxanthine derivatives as dual A2A antagonists/MAO‑B inhibitors.

    PubMed

    Bhayye, S S; Roy, K; Saha, A

    2016-02-12

    Dual inhibition of A2A and MAO-B is an emerging strategy in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, atom-based three-dimensional quantitative structure-activity relationship (3D-QSAR) and hologram quantitative structure-activity relationship (HQSAR) models were generated with benzothiazine and deazaxanthine derivatives. Based on activity against A2A and MAO-B, two statistically significant 3D-QSAR models (r(2) = 0.96, q(2) = 0.76 and r(2) = 0.91, q(2) = 0.63) and HQSAR models (r(2) = 0.93, q(2) = 0.68 and r(2) = 0.97, q(2) = 0.58) were developed. In an activity cliff analysis, structural outliers were identified by calculating the Mahalanobis distance for a pair of compounds with A2A and MAO-B inhibitory activities. The generated 3D-QSAR and HQSAR models, activity cliff analysis, molecular docking and dynamic studies for dual target protein inhibitors provide key structural scaffolds that serve as building blocks in designing drug-like molecules for neurodegenerative diseases.

  15. Atom-based 3D-QSAR, molecular docking and molecular dynamics simulation assessment of inhibitors for thyroid hormone receptor α and β.

    PubMed

    Gupta, Manish Kumar; Misra, Krishna

    2014-06-01

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitors of thyroid hormone receptors (TR) α and (TR) β was studied. The training set of the TRα model generated a correlation coefficient (R(2)) =  0.9535, with standard deviation (SD) =  0.3016. From the test set of the TRα model, a Q(2) value for the predicted activities (= 0.4303), squared correlation (random selection R(2)-CV  =  0.6929), Pearson-R (= 0.7294) and root mean square error (RMSE  =  0.6342) were calculated. The P-value for TRα (= 1.411e-96) and TRβ (= 2.108e-165) models indicate a high degree of self-reliance. For the TRβ model, the training set yielded R(2) = 0.9424 with SD = 0.3719. From the test set of TRβ, Q(2) value (= 0.5336), the squared correlation (R(2)-CV  =  0.7201), the Pearson-R (= 0.7852) and RMSE for test set predictions (= 0.8630) all strengthen the good predictive competence of the QSAR model derived. Examination of internal as well as external validation supports the rationality and good predictive ability of the best model. Molecular docking explained the conformations of molecules and important amino acid residues at the docking pocket, and a molecular dynamics simulation study further uncovered the binding process and validated the rationality of docking results. The findings not only lead to a better understanding of interactions between these antagonists and thyroid hormone receptors α and β, but also provide valuable information about the impact of structure on activity that will be very beneficial in the design of novel antagonists with preferred activity.

  16. Rigorous Incorporation of Tautomers, Ionization Species, and Different Binding Modes into Ligand-Based and Receptor-Based 3D-QSAR Methods

    PubMed Central

    Natesan, Senthil; Balaz, Stefan

    2013-01-01

    Speciation of drug candidates and receptors caused by ionization, tautomerism, and/or covalent hydration complicates ligand- and receptor-based predictions of binding affinities by 3-dimensional structure-activity relationships (3D-QSAR). The speciation problem is exacerbated by tendency of tautomers to bind in multiple conformations or orientations (modes) in the same binding site. New forms of the 3D-QSAR correlation equations, capable of capturing this complexity, can be developed using the time hierarchy of all steps that lie behind the monitored biological process – binding, enzyme inhibition or receptor activity. In most cases, reversible interconversions of individual ligand and receptor species can be treated as quickly established equilibria because they are finished in a small fraction of the exposure time that is used to determine biological effects. The speciation equilibria are satisfactorily approximated by invariant fractions of individual ligand and receptor species for buffered experimental or in vivo conditions. For such situations, the observed drug-receptor association constant of a ligand is expressed as the sum of products, for each ligand and receptor species pair, of the association microconstant and the fractions of involved species. For multiple binding modes, each microconstant is expressed as the sum of microconstants of individual modes. This master equation leads to new 3D-QSAR correlation equations integrating the results of all molecular simulations or calculations, which are run for each ligand-receptor species pair separately. The multispecies, multimode 3D-QSAR approach is illustrated by a ligand-based correlation of transthyretin binding of thyroxine analogs and by a receptor-based correlation of inhibition of MK2 by benzothiophenes and pyrrolopyrimidines. PMID:23170882

  17. Structural requirements of 3-carboxyl-4(1H)-quinolones as potential antimalarials from 2D and 3D QSAR analysis.

    PubMed

    Li, Jiazhong; Li, Shuyan; Bai, Chongliang; Liu, Huanxiang; Gramatica, Paola

    2013-07-01

    Malaria is a fatal tropical and subtropical disease caused by the protozoal species Plasmodium. Many commonly available antimalarial drugs and therapies are becoming ineffective because of the emergence of multidrug resistant Plasmodium falciparum, which drives the need for the development of new antimalarial drugs. Recently, a series of 3-carboxyl-4(1H)-quinolone analogs, derived from the famous compound endochin, were reported as promising candidates for orally efficacious antimalarials. In this study, to analyze the structure-activity relationships (SAR) of these quinolones and investigate the structural requirements for antimalarial activity, the 2D multiple linear regressions (MLR) method and 3D comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods are employed to evolve different QSAR models. All these models give satisfactory results with highly accurate fitting and strong external predictive abilities for chemicals not used in model development. Furthermore, the contour maps from 3D models can provide an intuitive understanding of the key structure features responsible for the antimalarial activities. In conclusion, we summarize the detailed position-specific structural requirements of these derivatives accordingly. All these results are helpful for the rational design of new compounds with higher antimalarial bioactivities.

  18. Novel substituted benzothiophene and thienothiophene carboxanilides and quinolones: synthesis, photochemical synthesis, DNA-binding properties, antitumor evaluation and 3D-derived QSAR analysis.

    PubMed

    Aleksić, Maja; Bertoša, Branimir; Nhili, Raja; Uzelac, Lidija; Jarak, Ivana; Depauw, Sabine; David-Cordonnier, Marie-Hélène; Kralj, Marijeta; Tomić, Sanja; Karminski-Zamola, Grace

    2012-06-14

    A series of new N,N-dimethylaminopropyl- and 2-imidazolinyl-substituted derivatives of benzo[b]thienyl- and thieno[2,3-b]thienylcarboxanilides and benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones were prepared. Quinolones were prepared by the reaction of photochemical dehydrohalogenation of corresponding anilides. Carboxanilides and quinolones were tested for the antiproliferative activity. 2-Imidazolinyl-substituted derivatives showed very prominent activity. By use of the experimentally obtained antitumor measurements, 3D-derived QSAR analysis was performed for the set of compounds. Highly predictive 3D-derived QSAR models were obtained, and molecular properties that have the highest impact on antitumor activity were identified. Carboxanilides 6a-c and quinolones 9a-c and 11a were evaluated for DNA binding propensities and topoisomerases I and II inhibition as part of their mechanism of action assessment. The evaluated differences in the mode of action nicely correlate with the results of the 3D-QSAR analysis. Taken together, the results indicate which modifications of the compounds from the series should further improve their anticancer properties.

  19. QSAR and molecular docking studies on oxindole derivatives as VEGFR-2 tyrosine kinase inhibitors.

    PubMed

    Kang, Cong-Min; Liu, Dong-Qing; Zhao, Xu-Hao; Dai, Ying-Jie; Cheng, Jia-Gao; Lv, Ying-Tao

    2016-01-01

    The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 30 oxindole derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis comparative molecular similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q(2)) was 0.777, the non-cross-validated value (R(2)) was 0.987, and the external cross-validated value ([Formula: see text]) was 0.72. And with the CoMSIA model, the corresponding q(2), R(2) and [Formula: see text] values were 0.710, 0.988 and 0.78, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. The binding mode obtained by molecular docking was in good agreement with the 3D-QSAR results. Based on the QSAR models and the docking binding mode, a set of new VEGFR-2 tyrosine kinase inhibitors were designed, which showed excellent predicting inhibiting potencies. The result revealed that both QSAR models have good predictive capability to guide the design and structural modification of homologic compounds. It is also helpful for further research and development of new VEGFR-2 tyrosine kinase inhibitors.

  20. A 3-D QSAR-BASED IDENTIFICATION ALGORITHM FOR POTENTIAL ESTROGEN RECEPTOR LIGANDS

    EPA Science Inventory

    Recent reports concerning the lethal effects of solar ultraviolet-B (UV-B) radiation on amphibians suggest that this stressor has the potential to impact some amphibian populations. In this study embryos and larvae of three anuran species, Rana pipiens, R. clamitans, and R. septe...

  1. Pharmacophore modeling, 3D-QSAR, and in silico ADME prediction of N-pyridyl and pyrimidine benzamides as potent antiepileptic agents.

    PubMed

    Malik, Ruchi; Mehta, Pakhuri; Srivastava, Shubham; Choudhary, Bhanwar Singh; Sharma, Manish

    2016-09-08

    Biological mechanism attributing mutations in KCNQ2/Q3 results in benign familial neonatal epilepsy (BFNE), a rare form of epilepsy and thus neglected. It offers a potential target for antiepileptic drug discovery. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of N-pyridyl and pyrimidine benzamides possessing KCNQ2/Q3 opening activity. The pharmacophore model generated contains one hydrogen bond donor (D), one hydrophobic (H), and two aromatic rings (R). They are the crucial molecular write-up detailing predicted binding efficacy of high affinity and low affinity ligands for KCNQ2/Q3 opening activity. Furthermore, it has been validated by using a biological correlation between pharmacophore hypothesis-based 3D-QSAR variables and functional fingerprints of openers responsible for the receptor binding and also by docking of these benzamides into the validated homology model. Excellent statistical computational tools of QSAR model such as good correlation coefficient (R(2 )>( )0.80), higher F value (F > 39), and excellent predictive power (Q(2) > 0.7) with low standard deviation (SD <0.3) strongly suggest that the developed model could be used for prediction of antiepileptic activity of newer analogs. A preliminary pharmacokinetic profile of these derivatives was also performed on the basis of QikProp predictions.

  2. N-tuple topological/geometric cutoffs for 3D N-linear algebraic molecular codifications: variability, linear independence and QSAR analysis.

    PubMed

    García-Jacas, C R; Marrero-Ponce, Y; Barigye, S J; Hernández-Ortega, T; Cabrera-Leyva, L; Fernández-Castillo, A

    2016-12-01

    Novel N-tuple topological/geometric cutoffs to consider specific inter-atomic relations in the QuBiLS-MIDAS framework are introduced in this manuscript. These molecular cutoffs permit the taking into account of relations between more than two atoms by using (dis-)similarity multi-metrics and the concepts related with topological and Euclidean-geometric distances. To this end, the kth two-, three- and four-tuple topological and geometric neighbourhood quotient (NQ) total (or local-fragment) spatial-(dis)similarity matrices are defined, to represent 3D information corresponding to the relations between two, three and four atoms of the molecular structures that satisfy certain cutoff criteria. First, an analysis of a diverse chemical space for the most common values of topological/Euclidean-geometric distances, bond/dihedral angles, triangle/quadrilateral perimeters, triangle area and volume was performed in order to determine the intervals to take into account in the cutoff procedures. A variability analysis based on Shannon's entropy reveals that better distribution patterns are attained with the descriptors based on the cutoffs proposed (QuBiLS-MIDAS NQ-MDs) with regard to the results obtained when all inter-atomic relations are considered (QuBiLS-MIDAS KA-MDs - 'Keep All'). A principal component analysis shows that the novel molecular cutoffs codify chemical information captured by the respective QuBiLS-MIDAS KA-MDs, as well as information not captured by the latter. Lastly, a QSAR study to obtain deeper knowledge of the contribution of the proposed methods was carried out, using four molecular datasets (steroids (STER), angiotensin converting enzyme (ACE), thermolysin inhibitors (THER) and thrombin inhibitors (THR)) widely used as benchmarks in the evaluation of several methodologies. One to four variable QSAR models based on multiple linear regression were developed for each compound dataset following the original division into training and test sets. The

  3. Theoretical studies on QSAR and mechanism of 2-indolinone derivatives as tubulin inhibitors

    NASA Astrophysics Data System (ADS)

    Liao, Si Yan; Qian, Li; Miao, Ti Fang; Lu, Hai Liang; Zheng, Kang Cheng

    The theoretical studies on three-dimensional quantitative structure activity relationship (3D-QSAR) and action mechanism of a series of 2-indolinone derivatives as tubulin inhibitors against human breast cancer cell line MDA-MB-231 have been carried out. The established 3D-QSAR model from the comparative molecular field analysis (CoMFA) shows not only significant statistical quality but also predictive ability, with high correlation coefficient (R2 = 0.986) and cross-validation coefficient (q2 = 0.683). In particular, the appropriate binding orientations and conformations of these 2-indolinone derivatives interacting with tubulin are located by docking study, and it is very interesting to find that the plot of the energy scores of these compounds in DOCK versus the corresponding experimental pIC50 values exhibits a considerable linear correlation. Therefore, the inhibition mechanism that 2-indolinone derivatives were regarded as tubulin inhibitors can be theoretically confirmed. Based on such an inhibition mechanism along with 3D-QSAR results, some important factors improving the activities of these compounds were discussed in detail. These factors can be summarized as follows: the H atom adopted as substituent R1, the substituent R2 with higher electropositivity and smaller bulk, the substituents R4-R6 (on the phenyl ring) with higher electropositivity and larger bulk, and so on. These results can offer useful theoretical references for understanding the action mechanism, designing more potent inhibitors, and predicting their activities prior to synthesis.

  4. Identification of novel histone deacetylase 1 inhibitors by combined pharmacophore modeling, 3D-QSAR analysis, in silico screening and Density Functional Theory (DFT) approaches

    NASA Astrophysics Data System (ADS)

    Choubey, Sanjay K.; Mariadasse, Richard; Rajendran, Santhosh; Jeyaraman, Jeyakanthan

    2016-12-01

    Overexpression of HDAC1, a member of Class I histone deacetylase is reported to be implicated in breast cancer. Epigenetic alteration in carcinogenesis has been the thrust of research for few decades. Increased deacetylation leads to accelerated cell proliferation, cell migration, angiogenesis and invasion. HDAC1 is pronounced as the potential drug target towards the treatment of breast cancer. In this study, the biochemical potential of 6-aminonicotinamide derivatives was rationalized. Five point pharmacophore model with one hydrogen-bond acceptor (A3), two hydrogen-bond donors (D5, D6), one ring (R12) and one hydrophobic group (H8) was developed using 6-aminonicotinamide derivatives. The pharmacophore hypothesis yielded a 3D-QSAR model with correlation-coefficient (r2 = 0.977, q2 = 0.801) and it was externally validated with (r2pred = 0.929, r2cv = 0.850 and r2m = 0.856) which reveals the statistical significance of the model having high predictive power. The model was then employed as 3D search query for virtual screening against compound libraries (Zinc, Maybridge, Enamine, Asinex, Toslab, LifeChem and Specs) in order to identify novel scaffolds which can be experimentally validated to design future drug molecule. Density Functional Theory (DFT) at B3LYP/6-31G* level was employed to explore the electronic features of the ligands involved in charge transfer reaction during receptor ligand interaction. Binding free energy (ΔGbind) calculation was done using MM/GBSA which defines the affinity of ligands towards the receptor.

  5. Impedance mammograph 3D phantom studies.

    PubMed

    Wtorek, J; Stelter, J; Nowakowski, A

    1999-04-20

    The results obtained using the Technical University of Gdansk Electroimpedance Mammograph (TUGEM) of a 3D phantom study are presented. The TUGEM system is briefly described. The hardware contains the measurement head and DSP-based identification modules controlled by a PC computer. A specially developed reconstruction algorithm, Regulated Correction Frequency Algebraic Reconstruction Technique (RCFART), is used to obtain 3D images. To visualize results, the Advance Visualization System (AVS) is used. It allows a powerful image processing on a fast workstation or on a high-performance computer. Results of three types of 3D conductivity perturbations used in the study (aluminum, Plexiglas, and cucumber) are shown. The relative volumes of perturbations less than 2% of the measurement chamber are easily evidenced.

  6. Searching for anthranilic acid-based thumb pocket 2 HCV NS5B polymerase inhibitors through a combination of molecular docking, 3D-QSAR and virtual screening.

    PubMed

    Vrontaki, Eleni; Melagraki, Georgia; Mavromoustakos, Thomas; Afantitis, Antreas

    2016-01-01

    A combination of the following computational methods: (i) molecular docking, (ii) 3-D Quantitative Structure Activity Relationship Comparative Molecular Field Analysis (3D-QSAR CoMFA), (iii) similarity search and (iv) virtual screening using PubChem database was applied to identify new anthranilic acid-based inhibitors of hepatitis C virus (HCV) replication. A number of known inhibitors were initially docked into the "Thumb Pocket 2" allosteric site of the crystal structure of the enzyme HCV RNA-dependent RNA polymerase (NS5B GT1b). Then, the CoMFA fields were generated through a receptor-based alignment of docking poses to build a validated and stable 3D-QSAR CoMFA model. The proposed model can be first utilized to get insight into the molecular features that promote bioactivity, and then within a virtual screening procedure, it can be used to estimate the activity of novel potential bioactive compounds prior to their synthesis and biological tests.

  7. A Cray T3D performance study

    SciTech Connect

    Nallana, A.; Kincaid, D.R.

    1996-05-01

    We carry out a performance study using the Cray T3D parallel supercomputer to illustrate some important features of this machine. Timing experiments show the speed of various basic operations while more complicated operations give some measure of its parallel performance.

  8. Review of synthesis, biological assay and QSAR studies of β-secretase inhibitors.

    PubMed

    Niño, Helena; García-Pintos, Isela; Rodríguez-Borges, José E; Escobar-Cubiella, Manolo; García-Mera, Xerardo; Prado-Prado, Francisco

    2011-12-01

    Alzheimer's disease (AD) is highly complex. While several pathologies characterize this disease, amyloid plaques, composed of the β-amyloid peptide, are hallmark neuropathological lesions in Alzheimer's disease brain. Indeed, a wealth of evidence suggests that β-amyloid is central to the pathophysiology of AD and is likely to play an early role in this intractable neurodegenerative disorder. The BACE-1 enzyme is essential for the generation of β-amyloid. BACE-1 knockout mice do not produce β-amyloid and are free from Alzheimer's associated pathologies, including neuronal loss and certain memory deficits. The fact that BACE-1 initiates the formation of β-amyloid, and the observation that BACE-1 levels are elevated in this disease provide direct and compelling reasons to develop therapies directed at BACE-1 inhibition, thus reducing β-amyloid and its associated toxicities. In this sense, quantitative structure-activity relationships (QSAR) could play an important role in studying these β-secretase inhibitors. QSAR models are necessary in order to guide the β-secretase synthesis. This work is aimed at reviewing different design and synthesis and computational studies for a very large and heterogeneous series of β-secretase inhibitors. First, we review design, synthesis, and Biological assay of β-secretase inhibitors. Next, we review 2D QSAR, 3D QSAR, CoMFA, CoMSIA and Docking with different compounds to find out the structural requirements. Next, we review QSAR studies using the method of Linear Discriminant Analysis (LDA) in order to understand the essential structural requirement for receptor binding for β- secretase inhibitors.

  9. 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.

  10. Drug Design for CNS Diseases: Polypharmacological Profiling of Compounds Using Cheminformatic, 3D-QSAR and Virtual Screening Methodologies

    PubMed Central

    Nikolic, Katarina; Mavridis, Lazaros; Djikic, Teodora; Vucicevic, Jelica; Agbaba, Danica; Yelekci, Kemal; Mitchell, John B. O.

    2016-01-01

    HIGHLIGHTS Many CNS targets are being explored for multi-target drug designNew databases and cheminformatic methods enable prediction of primary pharmaceutical target and off-targets of compoundsQSAR, virtual screening and docking methods increase the potential of rational drug design The diverse cerebral mechanisms implicated in Central Nervous System (CNS) diseases together with the heterogeneous and overlapping nature of phenotypes indicated that multitarget strategies may be appropriate for the improved treatment of complex brain diseases. Understanding how the neurotransmitter systems interact is also important in optimizing therapeutic strategies. Pharmacological intervention on one target will often influence another one, such as the well-established serotonin-dopamine interaction or the dopamine-glutamate interaction. It is now accepted that drug action can involve plural targets and that polypharmacological interaction with multiple targets, to address disease in more subtle and effective ways, is a key concept for development of novel drug candidates against complex CNS diseases. A multi-target therapeutic strategy for Alzheimer‘s disease resulted in the development of very effective Multi-Target Designed Ligands (MTDL) that act on both the cholinergic and monoaminergic systems, and also retard the progression of neurodegeneration by inhibiting amyloid aggregation. Many compounds already in databases have been investigated as ligands for multiple targets in drug-discovery programs. A probabilistic method, the Parzen-Rosenblatt Window approach, was used to build a “predictor” model using data collected from the ChEMBL database. The model can be used to predict both the primary pharmaceutical target and off-targets of a compound based on its structure. Several multi-target ligands were selected for further study, as compounds with possible additional beneficial pharmacological activities. Based on all these findings, it is concluded that multipotent

  11. Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1: molecular docking and 3D QSAR analyses.

    PubMed

    Liu, Hong; Huang, Xiaoqin; Shen, Jianhua; Luo, Xiaomin; Li, Minghui; Xiong, Bing; Chen, Gang; Shen, Jingkang; Yang, Yimin; Jiang, Hualiang; Chen, Kaixian

    2002-10-24

    The Lamarckian genetic algorithm of AutoDock 3.0 has been employed to dock 40 1,5-diarylpyrazole class compounds into the active sites of cyclooxygenase-2 (COX-2) and cyclooxygenase-1 (COX-1). The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The data of geometrical parameters and RMSD values compared with the known inhibitor, SC-558 (43), show that these inhibitors interact respectively with COX-2 and COX-1 in a very similar way. The r(2) values of 0.648 for COX-2 and 0.752 for COX-1 indicate that the calculated binding free energies correlate well with the inhibitory activities. The structural and energetic differences in inhibitory potencies of 1,5-diarylpyrazoles were reasonably explored, and the COX-2/COX-1 selectivity was demonstrated by the three-dimensional (3D) interaction models of inhibitors complexing with these two enzymes. Using the binding conformations of 1,5-diarylpyrazoles, consistent and highly predictive 3D quantitative structure-activity relationship (QSAR) models were developed by performing comparative molecular field analyses (CoMFA) and comparative molecular similarity analyses (CoMSIA). The q(2) values are 0.635 and 0.641 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by SC-558 (43) and a set of 10 other compounds that were not included in the training set. Mapping these models back to the topology of the active site of COX-2 leads to a better understanding of vital diarylpyrazole compounds and COX-2 interactions. Structure-based investigations and the final 3D QSAR results provided possible guidelines and accurate activity predictions for novel inhibitor design.

  12. Beowulf 3D: a case study

    NASA Astrophysics Data System (ADS)

    Engle, Rob

    2008-02-01

    This paper discusses the creative and technical challenges encountered during the production of "Beowulf 3D," director Robert Zemeckis' adaptation of the Old English epic poem and the first film to be simultaneously released in IMAX 3D and digital 3D formats.

  13. Microwave assistant one pot synthesis, crystal structure, antifungal activities and 3D-QSAR of novel 1,2,4-triazolo[4,3-a]pyridines.

    PubMed

    Liu, Xing-Hai; Sun, Zhao-Hui; Yang, Ming-Yan; Tan, Cheng-Xia; Weng, Jian-Quan; Zhang, Yong-Gang; Ma, Yi

    2014-09-01

    A series of novel 1,2,4-triazolo[4,3-a]pyridines were synthesized, and their structures were characterized by (1) H NMR, MS, elemental analysis, and single-crystal X-ray diffraction analysis. The antifungal activities were evaluated. The antifungal activity results indicated that the compound 2b, 2g, 2p, and 2i exhibited good activities. The activity of compound 2b, 2g, 2p, and 2i can compare with the commercial pesticide. The 3D-QSAR model was developed using CoMFA method. Both the steric and electronic field distributions of CoMFA are in good agreement in this work and will be very helpful in designing a new set of analogues.

  14. Comparative residue interaction analysis (CoRIA): a 3D-QSAR approach to explore the binding contributions of active site residues with ligands

    NASA Astrophysics Data System (ADS)

    Datar, Prasanna A.; Khedkar, Santosh A.; Malde, Alpeshkumar K.; Coutinho, Evans C.

    2006-06-01

    A novel approach termed comparative residue-interaction analysis (CoRIA), emphasizing the trends and principles of QSAR in a ligand-receptor environment has been developed to analyze and predict the binding affinity of enzyme inhibitors. To test this new approach, a training set of 36 COX-2 inhibitors belonging to nine families was selected. The putative binding (bioactive) conformations of inhibitors in the COX-2 active site were searched using the program DOCK. The docked configurations were further refined by a combination of Monte Carlo and simulated annealing methods with the Affinity program. The non-bonded interaction energies of the inhibitors with the individual amino acid residues in the active site were then computed. These interaction energies, plus specific terms describing the thermodynamics of ligand-enzyme binding, were correlated to the biological activity with G/PLS. The various QSAR models obtained were validated internally by cross validation and boot strapping, and externally using a test set of 13 molecules. The QSAR models developed on the CoRIA formalism were robust with good r 2, q 2 and r pred 2 values. The major highlights of the method are: adaptation of the QSAR formalism in a receptor setting to answer both the type (qualitative) and the extent (quantitative) of ligand-receptor binding, and use of descriptors that account for the complete thermodynamics of the ligand-receptor binding. The CoRIA approach can be used to identify crucial interactions of inhibitors with the enzyme at the residue level, which can be gainfully exploited in optimizing the inhibitory activity of ligands. Furthermore, it can be used with advantage to guide point mutation studies. As regards the COX-2 dataset, the CoRIA approach shows that improving Coulombic interaction with Pro528 and reducing van der Waals interaction with Tyr385 will improve the binding affinity of inhibitors.

  15. QSAR analyses of DDT analogues and their in silico validation using molecular docking study against voltage-gated sodium channel of Anopheles funestus.

    PubMed

    Saini, V; Kumar, A

    2014-01-01

    DDT has enjoyed the reputation of a successful pesticide in disease control programme and agricultural practices along with the serious opposition and ban later on due to its biomagnification and toxic action against non-target organisms. The present work was carried out to develop QSAR models for analysing DDT analogues for their pesticidal activity and in silico validation of these models. A 2D-QSAR model was generated using stepwise with multiple regression, and the model with a value of r(2) = 0.7324; q(2) = 0.6215; pred r(2) = 0.7038, containing five descriptors, was selected for further study. The 3D QSAR with CoMFA analysis showed that steric contribution of 21% and electrostatic contribution of about 79% were required for larvicidal activity of DDT analogues. A set of 3430 molecules was generated using the basic DDT skeleton as template, and these were evaluated for their mosquito larvicidal activity using the generated QSAR models and DDT as standard. Eleven molecules were selected for in silico validation of these models. For this, a docking study of the selected molecules against the homology-modelled voltage-gated sodium channel of Anopheles funestus was conducted. The study showed that the activities of these analogues as predicted by 2D-QSAR, 3D-QSAR with CoMFA and dock score were observed to be well correlated.

  16. Pharmacophore and 3D-QSAR Characterization of 6-Arylquinazolin-4-amines as Cdc2-like Kinase 4 (Clk4) and Dual Specificity Tyrosine-phosphorylation-regulated Kinase 1A (Dyrk1A) Inhibitors

    PubMed Central

    2013-01-01

    Cdc2-like kinase 4 (Clk4) and dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) are protein kinases that are promising targets for treatment of diseases caused by abnormal gene splicing. 6-Arylquinazolin-4-amines have been recently identified as potent Clk4 and Dyrk1A inhibitors. In order to understand the structure–activity correlation of these analogs, we have applied ligand-based pharmacophore and 3D-QSAR modeling combined with structure-based homology modeling and docking. The high R2 and Q2 (0.88 and 0.79 for Clk4, 0.85 and 0.82 for Dyrk1A, respectively) based on validation with training and test set compounds suggested that the generated 3D-QSAR models are reliable in predicting novel ligand activities against Clk4 and Dyrk1A. The binding mode identified through docking ligands to the ATP binding domain of Clk4 was consistent with the structural properties and energy field contour maps characterized by pharmacophore and 3D-QSAR models and gave valuable insights into the structure–activity profile of 6-arylquinazolin-4-amine analogs. The obtained 3D-QSAR and pharmacophore models in combination with the binding mode between inhibitor and residues of Clk4 will be helpful for future lead compound identification and optimization to design potent and selective Clk4 and Dyrk1A inhibitors. PMID:23496085

  17. Molecular modeling of histamine H3 receptor and QSAR studies on arylbenzofuran derived H3 antagonists.

    PubMed

    Dastmalchi, Siavoush; Hamzeh-Mivehroud, Maryam; Ghafourian, Taravat; Hamzeiy, Hossain

    2008-01-01

    Histamine H3 receptors are presynaptic autoreceptors found in both central and peripheral nervous systems of many species. The central effects of these receptors suggest a potential therapeutic role for their antagonists in treatment of several neurological disorders such as epilepsy, schizophrenia, Alzheimer's and Parkinson's diseases. The purpose of this study was to identify the structural requirements for H3 antagonistic activity via quantitative structure-activity relationship (QSAR) studies and receptor modeling/docking techniques. A combination of partial least squares (PLS) and genetic algorithm (GA) was used in the QSAR approach to select the structural descriptors relevant to the receptor binding affinity of a series of 58 H3 antagonists. The descriptors were selected out of a pool of >1000 descriptors calculated by DRAGON, Hyperchem and ACD labs suite of programs. The resulting QSAR models for rat and human H3 binding affinities were validated using different strategies. QSAR models generated in the current work suggested the role of charge transfer interactions in the ligand-receptor interaction verified using the molecular modeling of the receptor and docking two antagonists to the binding site. The 3D model of human H3 receptor was built based on bovine rhodopsin structure and evaluated by molecular dynamics (MD) simulation in a mixed water-vacuum-water environment. The results were indicative of the stability of the model relating the observed structural changes during the MD simulation to the suggested ligand-receptor interactions. The results of this investigation are expected to be useful in the process of design and development of new potent H3 receptor antagonists.

  18. Case study: Beauty and the Beast 3D: benefits of 3D viewing for 2D to 3D conversion

    NASA Astrophysics Data System (ADS)

    Handy Turner, Tara

    2010-02-01

    From the earliest stages of the Beauty and the Beast 3D conversion project, the advantages of accurate desk-side 3D viewing was evident. While designing and testing the 2D to 3D conversion process, the engineering team at Walt Disney Animation Studios proposed a 3D viewing configuration that not only allowed artists to "compose" stereoscopic 3D but also improved efficiency by allowing artists to instantly detect which image features were essential to the stereoscopic appeal of a shot and which features had minimal or even negative impact. At a time when few commercial 3D monitors were available and few software packages provided 3D desk-side output, the team designed their own prototype devices and collaborated with vendors to create a "3D composing" workstation. This paper outlines the display technologies explored, final choices made for Beauty and the Beast 3D, wish-lists for future development and a few rules of thumb for composing compelling 2D to 3D conversions.

  19. New series of morpholine and 1,4-oxazepane derivatives as dopamine D4 receptor ligands: synthesis and 3D-QSAR model.

    PubMed

    Audouze, Karine; Nielsen, Elsebet Østergaard; Peters, Dan

    2004-06-03

    Since the identification of the dopamine D(4) receptor subtype and speculations about its possible involvement in schizophrenia, much work has been put into development of selective D(4) ligands. These selective ligands may be effective antipsychotics without extrapyramidal side effects. This work describes the synthesis of a new series of 2,4-disubstituted morpholines and 2,4-disubstituted 1,4-oxazepanes with selectivity for the dopamine D(4) receptor. A 3D-QSAR analysis using the GRID/GOLPE methodology was performed with the purpose to get a better understanding of the relationship between chemical structure and biological activity. Inspection of the coefficient plots allowed us to identify that regions which are important for affinity are situated around the two benzene ring systems, a p-chlorobenzyl group, and the aliphatic amine belonging to the morpholine or 1,4-oxazepane system. In addition, the size of the morpholine or 1,4-oxazepane ring seems to be important for affinity.

  20. CASTOR3D: linear stability studies for 2D and 3D tokamak equilibria

    NASA Astrophysics Data System (ADS)

    Strumberger, E.; Günter, S.

    2017-01-01

    The CASTOR3D code, which is currently under development, is able to perform linear stability studies for 2D and 3D, ideal and resistive tokamak equilibria in the presence of ideal and resistive wall structures and coils. For these computations ideal equilibria represented by concentric nested flux surfaces serve as input (e.g. computed with the NEMEC code). Solving an extended eigenvalue problem, the CASTOR3D code takes simultaneously plasma inertia and wall resistivity into account. The code is a hybrid of the CASTOR_3DW stability code and the STARWALL code. The former is an extended version of the CASTOR and CASTOR_FLOW code, respectively. The latter is a linear 3D code computing the growth rates of resistive wall modes in the presence of multiply-connected wall structures. The CASTOR_3DW code, and some parts of the STARWALL code have been reformulated in a general 3D flux coordinate representation that allows to choose between various types of flux coordinates. Furthermore, the implemented many-valued current potentials in the STARWALL part allow a correct treatment of the m  =  0, n  =  0 perturbation. In this paper, we outline the theoretical concept, and present some numerical results which illustrate the present status of the code and demonstrate its numerous application possibilities.

  1. Understanding the Molecular Determinant of Reversible Human Monoamine Oxidase B Inhibitors Containing 2H-chromen-2-One Core: Structure-Based and Ligand-Based Derived 3-D QSAR Predictive Models.

    PubMed

    Mladenovic, Milan; Patsilinakos, Alexandros; Pirolli, Adele; Sabatino, Manuela; Ragno, Rino

    2017-03-14

    Monoamine oxidase B (MAO B) catalyzes the oxidative deamination of aryalkylamines neurotransmitters with concomitant reduction of oxygen to hydrogen peroxide. Consequently, the enzyme's malfunction can induce oxidative damage to mitochondrial DNA and mediates development of Parkinson's disease. Thus, MAO B emerges as a promising target for developing pharmaceuticals potentially useful to treat this vicious neurodegenerative condition. Aiming to contribute to the development of drugs with the reversible mechanism of MAO B inhibition only, herein, an extended in silico-in vitro procedure for the selection of novel MAO B inhibitors is demonstrated, including: (1) definition of optimized and validated structure-based (SB) 3-D QSAR models derived from available co-crystallized inhibitor-MAO B complexes; (2) elaboration of structure-activity relationships (SAR) features for either irreversible or reversible MAO B inhibitors to characterize and improve coumarin-based inhibitor activity (Protein Data Bank ID: 2V61) as the most potent reversible lead compound; (3) definition of structure-based (SB) and ligand-based (LB) alignment rules assessments by which virtually any untested potential MAO B inhibitor might be evaluated; (4) predictive ability validation of the best 3-D QSAR model through SB/LB modeling of four coumarin-based external test sets (267 compounds); (5) design and SB/LB alignment of novel coumarin-based scaffolds experimentally validated through synthesis and biological evaluation in vitro. Due to the wide range of molecular diversity within the 3-D QSARs training set and derived features, the selected N probe-derived 3-D QSAR model proves to be a valuable tool for virtual screening (VS) of novel MAO B inhibitors and a platform for design, synthesis and evaluation of novel active structures. Accordingly, six highly active and selective MAO B inhibitors (picomolar to low nanomolar range of activity) were disclosed as a result of rational SB/LB 3-D QSAR design

  2. Insights on Cytochrome P450 Enzymes and Inhibitors Obtained Through QSAR Studies

    PubMed Central

    Sridhar, Jayalakshmi; Liu, Jiawang; Foroozesh, Maryam; Stevens, Cheryl L. Klein

    2013-01-01

    The cytochrome P450 (CYP) superfamily of heme enzymes play an important role in the metabolism of a large number of endogenous and exogenous compounds, including most of the drugs currently on the market. Inhibitors of CYP enzymes have important roles in the treatment of several disease conditions such as numerous cancers and fungal infections in addition to their critical role in drug-drug interactions. Structure activity relationships (SAR), and three-dimensional quantitative structure activity relationships (3D-QSAR) represent important tools in understanding the interactions of the inhibitors with the active sites of the CYP enzymes. A comprehensive account of the QSAR studies on the major human CYPs 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, 3A4 and a few other CYPs are detailed in this review which will provide us with an insight into the individual/common characteristics of the active sites of these enzymes and the enzyme-inhibitor interactions. PMID:22864238

  3. Finding new scaffolds of JAK3 inhibitors in public database: 3D-QSAR models & shape-based screening.

    PubMed

    Gadhe, Changdev G; Lee, Eunhee; Kim, Mi-Hyun

    2015-11-01

    The STAT/JAK3 pathway is a well-known therapeutic target in various diseases (ex. rheumatoid arthritis and psoriasis). The therapeutic advantage of JAK3 inhibition motivated to find new scaffolds with desired DMPK. For the purpose, in silico high-throughput sieves method is developed consisting of a receptor-guided three-dimensional quantitative structure-activity relationship study and shape-based virtual screening. We developed robust and predictive comparative molecular field analysis (q (2) = 0.760, r (2) = 0.915) and comparative molecular similarity index analysis (q (2) = 0.817, r (2) = 0.981) models and validated these using a test set, which produced satisfactory predictions of 0.925 and 0.838, respectively.

  4. Hologram QSAR studies of antiprotozoal activities of sesquiterpene lactones.

    PubMed

    Trossini, Gustavo H G; Maltarollo, Vinícius G; Schmidt, Thomas J

    2014-07-18

    Infectious diseases such as trypanosomiasis and leishmaniasis are considered neglected tropical diseases due the lack for many years of research and development into new drug treatments besides the high incidence of mortality and the lack of current safe and effective drug therapies. Natural products such as sesquiterpene lactones have shown activity against T. brucei and L. donovani, the parasites responsible for these neglected diseases. To evaluate structure activity relationships, HQSAR models were constructed to relate a series of 40 sesquiterpene lactones (STLs) with activity against T. brucei, T. cruzi, L. donovani and P. falciparum and also with their cytotoxicity. All constructed models showed good internal (leave-one-out q2 values ranging from 0.637 to 0.775) and external validation coefficients (r2test values ranging from 0.653 to 0.944). From HQSAR contribution maps, several differences between the most and least potent compounds were found. The fragment contribution of PLS-generated models confirmed the results of previous QSAR studies that the presence of α,β-unsatured carbonyl groups is fundamental to biological activity. QSAR models for the activity of these compounds against T. cruzi, L. donovani and P. falciparum are reported here for the first time. The constructed HQSAR models are suitable to predict the activity of untested STLs.

  5. Molecular modeling studies of phenoxypyrimidinyl imidazoles as p38 kinase inhibitors using QSAR and docking.

    PubMed

    Ravindra, G K; Achaiah, G; Sastry, G N

    2008-04-01

    p38 Kinase plays a vital role in inflammation mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) pathways and inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Pyridinyl and pyrimidinyl imidazoles, selectively inhibit p38alpha MAP kinase, are useful in the treatment of inflammatory diseases like rheumatoid arthritis. Three dimensional quantitative structure-activity relationship studies (3D-QSAR) involving comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) and molecular docking were performed on 44 phenoxypyrimidinyl imidazole p38 kinase inhibitors to find out the structural relationship with the activity. The best predictive CoMFA model with atom fit alignment resulted in cross-validated r(2) value of 0.553, noncross-validated r(2) value of 0.908 and standard error of estimate 0.187. Similarly the best predictive CoMSIA model was derived with q(2) of 0.508, noncross-validated r(2) of 0.894 and standard error of estimate of 0.197, comprising steric, electrostatic, hydrophobic and hydrogen bond donor fields. These models were able to predict the activity of test set molecules efficiently within an acceptable error range. GOLD and FlexX were employed to dock the inhibitors into the active site of the p38 kinase and these docking studies revealed the vital interactions and binding conformation of the inhibitors. The information rendered by 3D-QSAR models and the docking interactions may afford valuable clues to optimize the lead and design new potential inhibitors.

  6. Analysis of stereoelectronic properties, mechanism of action and pharmacophore of synthetic indolo[2,1-b]quinazoline-6,12-dione derivatives in relation to antileishmanial activity using quantum chemical, cyclic voltammetry and 3-D-QSAR CATALYST procedures.

    PubMed

    Bhattacharjee, Apurba K; Skanchy, David J; Jennings, Barton; Hudson, Thomas H; Brendle, James J; Werbovetz, Karl A

    2002-06-01

    Several indolo[2,1-b]quinazoline-6,12-dione (tryptanthrin) derivatives exhibited remarkable activity at concentrations below 100 ng/mL when tested against in vitro Leishmania donovani amastigotes. The in vitro toxicity studies indicate that the compounds are fairly well tolerated in both macrophage and neuronal lines. An analysis based on qualitative and quantitative structure-activity relationship studies between in vitro antileishmanial activity and molecular electronic structure of 27 analogues of indolo[2,1-b]quinazoline-6,12-dione is presented here by using a combination of semi-empirical AM1 quantum chemical, cyclic voltammetry and a pharmacophore generation (CATALYST) methods. A modest to good correlation is observed between activity and a few calculated molecular properties such as molecular density, octanol-water partition coefficient, molecular orbital energies, and redox potentials. Electron transfer seems to be a plausible path in the mechanism of action of the compounds. A pharmacophore generated by using the 3-D QSAR of CATALYST produced a fairly accurate predictive model of antileishmanial activity of the tryptanthrins. The validity of the pharmacophore model extends to structurally different class of compounds that could open new frontiers for study. The carbonyl group of the five- and six-membered rings in the indolo[2,1-b]quinazoline-6,12-dione skeleton and the electron transfer ability to the carbonyl atom appear to be crucial for activity.

  7. QSAR analyses of organophosphates for insecticidal activity and its in-silico validation using molecular docking study.

    PubMed

    Niraj, Ravi Ranjan Kumar; Saini, Vandana; Kumar, Ajit

    2015-11-01

    The present work was carried out to design and develop novel QSAR models using 2D-QSAR and 3D-QSAR with CoMFA methodology for prediction of insecticidal activity of organophosphate (OP) molecules. The models were validated on an entirely different external dataset of in-house generated combinatorial library of OPs, by completely different computational approach of molecular docking against the target AChE protein of Musca domestica. The dock scores were observed to be in good correlation with 2D-QSAR and 3D-QSAR with CoMFA predicted activities and had the correlation coefficients (r(2)) of -0.62 and -0.63, respectively. The activities predicted by 2D-QSAR and 3D-QSAR with CoMFA were also observed to be highly correlated with r(2)=0.82. Also, the combinatorial library molecules were screened for toxicity in non-target organisms and degradability using USEPA-EPI Suite. The work was first step towards computer aided design and development of novel OP pesticide candidates with good insecticidal property but lower toxicity in non-targeted organisms and having biodegradation potential.

  8. 2D vs. 3D mammography observer study

    NASA Astrophysics Data System (ADS)

    Fernandez, James Reza F.; Hovanessian-Larsen, Linda; Liu, Brent

    2011-03-01

    Breast cancer is the most common type of non-skin cancer in women. 2D mammography is a screening tool to aid in the early detection of breast cancer, but has diagnostic limitations of overlapping tissues, especially in dense breasts. 3D mammography has the potential to improve detection outcomes by increasing specificity, and a new 3D screening tool with a 3D display for mammography aims to improve performance and efficiency as compared to 2D mammography. An observer study using a mammography phantom was performed to compare traditional 2D mammography with this ne 3D mammography technique. In comparing 3D and 2D mammography there was no difference in calcification detection, and mass detection was better in 2D as compared to 3D. There was a significant decrease in reading time for masses, calcifications, and normals in 3D compared to 2D, however, as well as more favorable confidence levels in reading normal cases. Given the limitations of the mammography phantom used, however, a clearer picture in comparing 3D and 2D mammography may be better acquired with the incorporation of human studies in the future.

  9. Image based 3D city modeling : Comparative study

    NASA Astrophysics Data System (ADS)

    Singh, S. P.; Jain, K.; Mandla, V. R.

    2014-06-01

    3D city model is a digital representation of the Earth's surface and it's related objects such as building, tree, vegetation, and some manmade feature belonging to urban area. The demand of 3D city modeling is increasing rapidly for various engineering and non-engineering applications. Generally four main image based approaches were used for virtual 3D city models generation. In first approach, researchers were used Sketch based modeling, second method is Procedural grammar based modeling, third approach is Close range photogrammetry based modeling and fourth approach is mainly based on Computer Vision techniques. SketchUp, CityEngine, Photomodeler and Agisoft Photoscan are the main softwares to represent these approaches respectively. These softwares have different approaches & methods suitable for image based 3D city modeling. Literature study shows that till date, there is no complete such type of comparative study available to create complete 3D city model by using images. This paper gives a comparative assessment of these four image based 3D modeling approaches. This comparative study is mainly based on data acquisition methods, data processing techniques and output 3D model products. For this research work, study area is the campus of civil engineering department, Indian Institute of Technology, Roorkee (India). This 3D campus acts as a prototype for city. This study also explains various governing parameters, factors and work experiences. This research work also gives a brief introduction, strengths and weakness of these four image based techniques. Some personal comment is also given as what can do or what can't do from these softwares. At the last, this study shows; it concluded that, each and every software has some advantages and limitations. Choice of software depends on user requirements of 3D project. For normal visualization project, SketchUp software is a good option. For 3D documentation record, Photomodeler gives good result. For Large city

  10. M3D project for simulation studies of plasmas

    SciTech Connect

    Park, W.; Belova, E.V.; Fu, G.Y.; Strauss, H.R.; Sugiyama, L.E.

    1998-12-31

    The M3D (Multi-level 3D) project carries out simulation studies of plasmas of various regimes using multi-levels of physics, geometry, and mesh schemes in one code package. This paper and papers by Strauss, Sugiyama, and Belova in this workshop describe the project, and present examples of current applications. The currently available physics models of the M3D project are MHD, two-fluids, gyrokinetic hot particle/MHD hybrid, and gyrokinetic particle ion/two-fluid hybrid models. The code can be run with both structured and unstructured meshes.

  11. Autonomous surgical robotics using 3-D ultrasound guidance: feasibility study.

    PubMed

    Whitman, John; Fronheiser, Matthew P; Ivancevich, Nikolas M; Smith, Stephen W

    2007-10-01

    The goal of this study was to test the feasibility of using a real-time 3D (RT3D) ultrasound scanner with a transthoracic matrix array transducer probe to guide an autonomous surgical robot. Employing a fiducial alignment mark on the transducer to orient the robot's frame of reference and using simple thresholding algorithms to segment the 3D images, we tested the accuracy of using the scanner to automatically direct a robot arm that touched two needle tips together within a water tank. RMS measurement error was 3.8% or 1.58 mm for an average path length of 41 mm. Using these same techniques, the autonomous robot also performed simulated needle biopsies of a cyst-like lesion in a tissue phantom. This feasibility study shows the potential for 3D ultrasound guidance of an autonomous surgical robot for simple interventional tasks, including lesion biopsy and foreign body removal.

  12. A Preliminary Study of 3D Printing on Rock Mechanics

    NASA Astrophysics Data System (ADS)

    Jiang, Chao; Zhao, Gao-Feng

    2015-05-01

    3D printing is an innovative manufacturing technology that enables the printing of objects through the accumulation of successive layers. This study explores the potential application of this 3D printing technology for rock mechanics. Polylactic acid (PLA) was used as the printing material, and the specimens were constructed with a "3D Touch" printer that employs fused deposition modelling (FDM) technology. Unconfined compressive strength (UCS) tests and direct tensile strength (DTS) tests were performed to determine the Young's modulus ( E) and Poisson's ratio ( υ) for these specimens. The experimental results revealed that the PLA specimens exhibited elastic to brittle behaviour in the DTS tests and exhibited elastic to plastic behaviour in the UCS tests. The influence of structural changes in the mechanical response of the printed specimen was investigated; the results indicated that the mechanical response is highly influenced by the input structures, e.g., granular structure, and lattice structure. Unfortunately, our study has demonstrated that the FDM 3D printing with PLA is unsuitable for the direct simulation of rock. However, the ability for 3D printing on manufactured rock remains appealing for researchers of rock mechanics. Additional studies should focus on the development of an appropriate substitution for the printing material (brittle and stiff) and modification of the printing technology (to print 3D grains with arbitrary shapes).

  13. NGT-3D: a simple nematode cultivation system to study Caenorhabditis elegans biology in 3D

    PubMed Central

    Lee, Tong Young; Yoon, Kyoung-hye; Lee, Jin Il

    2016-01-01

    ABSTRACT The nematode Caenorhabditis elegans is one of the premier experimental model organisms today. In the laboratory, they display characteristic development, fertility, and behaviors in a two dimensional habitat. In nature, however, C. elegans is found in three dimensional environments such as rotting fruit. To investigate the biology of C. elegans in a 3D controlled environment we designed a nematode cultivation habitat which we term the nematode growth tube or NGT-3D. NGT-3D allows for the growth of both nematodes and the bacteria they consume. Worms show comparable rates of growth, reproduction and lifespan when bacterial colonies in the 3D matrix are abundant. However, when bacteria are sparse, growth and brood size fail to reach levels observed in standard 2D plates. Using NGT-3D we observe drastic deficits in fertility in a sensory mutant in 3D compared to 2D, and this defect was likely due to an inability to locate bacteria. Overall, NGT-3D will sharpen our understanding of nematode biology and allow scientists to investigate questions of nematode ecology and evolutionary fitness in the laboratory. PMID:26962047

  14. NGT-3D: a simple nematode cultivation system to study Caenorhabditis elegans biology in 3D.

    PubMed

    Lee, Tong Young; Yoon, Kyoung-Hye; Lee, Jin Il

    2016-04-15

    The nematodeCaenorhabditiselegansis one of the premier experimental model organisms today. In the laboratory, they display characteristic development, fertility, and behaviors in a two dimensional habitat. In nature, however,C. elegansis found in three dimensional environments such as rotting fruit. To investigate the biology ofC. elegansin a 3D controlled environment we designed a nematode cultivation habitat which we term the nematode growth tube or NGT-3D. NGT-3D allows for the growth of both nematodes and the bacteria they consume. Worms show comparable rates of growth, reproduction and lifespan when bacterial colonies in the 3D matrix are abundant. However, when bacteria are sparse, growth and brood size fail to reach levels observed in standard 2D plates. Using NGT-3D we observe drastic deficits in fertility in a sensory mutant in 3D compared to 2D, and this defect was likely due to an inability to locate bacteria. Overall, NGT-3D will sharpen our understanding of nematode biology and allow scientists to investigate questions of nematode ecology and evolutionary fitness in the laboratory.

  15. 3D MI-DRAGON: new model for the reconstruction of US FDA drug- target network and theoretical-experimental studies of inhibitors of rasagiline derivatives for AChE.

    PubMed

    Prado-Prado, Francisco; García-Mera, Xerardo; Escobar, Manuel; Alonso, Nerea; Caamaño, Olga; Yañez, Matilde; González-Díaz, Humberto

    2012-01-01

    The number of neurodegenerative diseases has been increasing in recent years. Many of the drug candidates to be used in the treatment of neurodegenerative diseases present specific 3D structural features. An important protein in this sense is the acetylcholinesterase (AChE), which is the target of many Alzheimer's dementia drugs. Consequently, the prediction of Drug-Protein Interactions (DPIs/nDPIs) between new drug candidates and specific 3D structure and targets is of major importance. To this end, we can use Quantitative Structure-Activity Relationships (QSAR) models to carry out a rational DPIs prediction. Unfortunately, many previous QSAR models developed to predict DPIs take into consideration only 2D structural information and codify the activity against only one target. To solve this problem we can develop some 3D multi-target QSAR (3D mt-QSAR) models. In this study, using the 3D MI-DRAGON technique, we have introduced a new predictor for DPIs based on two different well-known software. We have used the MARCH-INSIDE (MI) and DRAGON software to calculate 3D structural parameters for drugs and targets respectively. Both classes of 3D parameters were used as input to train Artificial Neuronal Network (ANN) algorithms using as benchmark dataset the complex network (CN) made up of all DPIs between US FDA approved drugs and their targets. The entire dataset was downloaded from the DrugBank database. The best 3D mt-QSAR predictor found was an ANN of Multi-Layer Perceptron-type (MLP) with profile MLP 37:37-24-1:1. This MLP classifies correctly 274 out of 321 DPIs (Sensitivity = 85.35%) and 1041 out of 1190 nDPIs (Specificity = 87.48%), corresponding to training Accuracy = 87.03%. We have validated the model with external predicting series with Sensitivity = 84.16% (542/644 DPIs; Specificity = 87.51% (2039/2330 nDPIs) and Accuracy = 86.78%. The new CNs of DPIs reconstructed from US FDA can be used to explore large DPI databases in order to discover both new drugs

  16. Ligand Biological Activity Predictions Using Fingerprint-Based Artificial Neural Networks (FANN-QSAR)

    PubMed Central

    Myint, Kyaw Z.; Xie, Xiang-Qun

    2015-01-01

    This chapter focuses on the fingerprint-based artificial neural networks QSAR (FANN-QSAR) approach to predict biological activities of structurally diverse compounds. Three types of fingerprints, namely ECFP6, FP2, and MACCS, were used as inputs to train the FANN-QSAR models. The results were benchmarked against known 2D and 3D QSAR methods, and the derived models were used to predict cannabinoid (CB) ligand binding activities as a case study. In addition, the FANN-QSAR model was used as a virtual screening tool to search a large NCI compound database for lead cannabinoid compounds. We discovered several compounds with good CB2 binding affinities ranging from 6.70 nM to 3.75 μM. The studies proved that the FANN-QSAR method is a useful approach to predict bioactivities or properties of ligands and to find novel lead compounds for drug discovery research. PMID:25502380

  17. 2D QSAR Study for Gemfibrozil Glucuronide as the Mechanism-based Inhibitor of CYP2C8

    PubMed Central

    Taxak, N.; Bharatam, P. V.

    2013-01-01

    Mechanism-based inhibition of cytochrome P450 involves the bioactivation of the drug to a reactive metabolite, which leads to cytochrome inhibition via various mechanisms. This is generally seen in the Phase I of drug metabolism. However, gemfibrozil (hypolipidemic drug) leads to mechanism-based inhibition after generating glucuronide conjugate (gemfibrozil acyl-β-glucuronide) in the Phase II metabolism reaction. The mechanism involves the covalent binding of the benzyl radical (generated from the oxidation of aromatic methyl group in conjugate) to the heme of CYP2C8. This article deals with the development of a 2D QSAR model based on the inhibitory potential of gemfibrozil, its analogues and corresponding glucuronide conjugates in inhibiting the CYP2C8-catalysed amodiaquine N-deethylation. The 2D QSAR model was developed using multiple linear regression analysis in Accelrys Discovery Studio 2.5 and helps in identifying the descriptors, which are actually contributing to the inhibitory potency of the molecules studied. The built model was further validated using leave one out method. The best quantitative structure activity relationship model was selected having a correlation coefficient (r) of 0.814 and cross-validated correlation coefficient (q2) of 0.799. 2D QSAR revealed the importance of volume descriptor (Mor15v), shape descriptor (SP09) and 3D matrix-based descriptor (SpMax_RG) in defining the activity for this series of molecules. It was observed that volume and 3D matrix-based descriptors were crucial in imparting higher potency to gemfibrozil glucuronide conjugate, as compared with other molecules. The results obtained from the present study may be useful in predicting the inhibitory potential (IC50 for CYP2C8 inhibition) of the glucuronide conjugates of new molecules and compare with the standard gemfibrozil acyl-β-glucuronide (in terms of pIC50 values) in early stages of drug discovery and development. PMID:24591743

  18. Synthesis and QSAR study of novel anti-inflammatory active mesalazine-metronidazole conjugates.

    PubMed

    Naumov, Roman N; Panda, Siva S; Girgis, Adel S; George, Riham F; Farhat, Michel; Katritzky, Alan R

    2015-06-01

    Novel, mesalazine, metronidazole conjugates 6a-e with amino acid linkers were synthesized utilizing benzotriazole chemistry. Biological data acquired for all the novel bis-conjugates showed (a) some bis-conjugates exhibit comparable anti-inflammatory activity with parent drugs and (b) the potent bis-conjugates show no visible stomach lesions. 3D-pharmacophore and 2D-QSAR modeling support the observed bio-properties.

  19. 3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands.

    PubMed

    Lozano, J J; Pastor, M; Cruciani, G; Gaedt, K; Centeno, N B; Gago, F; Sanz, F

    2000-05-01

    Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes identified the most important enzyme-ligand interactions that account for the differences in activity within the series. A GRID/GOLPE analysis was then performed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and confirmed the advantages of incorporating structural information from series of ligand-receptor complexes into 3D-QSAR methodologies.

  20. 3D-QSAR methods on the basis of ligand-receptor complexes. Application of COMBINE and GRID/GOLPE methodologies to a series of CYP1A2 ligands

    NASA Astrophysics Data System (ADS)

    Lozano, Juan José; Pastor, Manuel; Cruciani, Gabriele; Gaedt, Katrin; Centeno, Nuria B.; Gago, Federico; Sanz, Ferran

    2000-05-01

    Many heterocyclic amines (HCA) present in cooked food exert a genotoxic activity when they are metabolised (N-oxidated) by the human cytochrome P450 1A2 (CYP1A2h). In order to rationalize the observed differences in activity of this enzyme on a series of 12 HCA, 3D-QSAR methods were applied on the basis of models of HCA-CYP1A2h complexes. The CYP1A2h enzyme model has been previously reported and was built by homology modeling based on cytochrome P450 BM3. The complexes were automatically generated applying the AUTODOCK software and refined using AMBER. A COMBINE analysis on the complexes identified the most important enzyme-ligand interactions that account for the differences in activity within the series. A GRID/GOLPE analysis was then performed on just the ligands, in the conformations and orientations found in the modeled complexes. The results from both methods were concordant and confirmed the advantages of incorporating structural information from series of ligand-receptor complexes into 3D-QSAR methodologies.

  1. Study of capabilities and limitations of 3D printing technology

    NASA Astrophysics Data System (ADS)

    Lemu, H. G.

    2012-04-01

    3D printing is one of the developments in rapid prototyping technology. The inception and development of the technology has highly assisted the product development phase of product design and manufacturing. The technology is particularly important in educating product design and 3D modeling because it helps students to visualize their design idea, to enhance their creative design process and enables them to touch and feel the result of their innovative work. The availability of many 3D printers on the market has created a certain level of challenge for the user. Among others, complexity of part geometry, material type, compatibility with 3D CAD models and other technical aspects still need in-depth study. This paper presents results of the experimental work on the capabilities and limitations of the Z510 3D printer from Z-corporation. Several parameters such as dimensional and geometrical accuracy, surface quality and strength as a function of model size, orientation and file exchange format are closely studied.

  2. 3D Geo-Information in Urban Climate Studies

    NASA Astrophysics Data System (ADS)

    Petrescu, F.; Aldea, M.; Luca, O.; Iacoboaea, C.; Gaman, F.; Parlow, E.

    2016-10-01

    3D geo-information is essential for urban climate studies. It is obvious that both natural environment and built-up environment play the fundamental role in defining the climatic conditions for urban areas, which affect the quality of human life and human comfort. The paper presents the main categories of 3D geo-information used in urban climate studies and roles in creating and operating the numerical models specially designed to simulate urban planning scenarios and improvement of the urban climate situation.

  3. 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

  4. Photogrammetric 3D skull/photo superimposition: A pilot study.

    PubMed

    Santoro, Valeria; Lubelli, Sergio; De Donno, Antonio; Inchingolo, Alessio; Lavecchia, Fulvio; Introna, Francesco

    2017-04-01

    The identification of bodies through the examination of skeletal remains holds a prominent place in the field of forensic investigations. Technological advancements in 3D facial acquisition techniques have led to the proposal of a new body identification technique that involves a combination of craniofacial superimposition and photogrammetry. The aim of this study was to test the method by superimposing various computerized 3D images of skulls onto various photographs of missing people taken while they were still alive in cases when there was a suspicion that the skulls in question belonged to them. The technique is divided into four phases: preparatory phase, 3d acquisition phase, superimposition phase, and metric image analysis 3d. The actual superimposition of the images was carried out in the fourth step. and was done so by comparing the skull images with the selected photos. Using a specific software, the two images (i.e. the 3D avatar and the photo of the missing person) were superimposed. Cross-comparisons of 5 skulls discovered in a mass grave, and of 2 skulls retrieved in the crawlspace of a house were performed. The morphologyc phase reveals a full overlap between skulls and photos of disappeared persons. Metric phase reveals that correlation coefficients of this values, higher than 0.998-0,997 allow to confirm identification hypothesis.

  5. Case study: The Avengers 3D: cinematic techniques and digitally created 3D

    NASA Astrophysics Data System (ADS)

    Clark, Graham D.

    2013-03-01

    Marvel's THE AVENGERS was the third film Stereo D collaborated on with Marvel; it was a summation of our artistic development of what Digitally Created 3D and Stereo D's artists and toolsets affords Marvel's filmmakers; the ability to shape stereographic space to support the film and story, in a way that balances human perception and live photography. We took our artistic lead from the cinematic intentions of Marvel, the Director Joss Whedon, and Director of Photography Seamus McGarvey. In the digital creation of a 3D film from a 2D image capture, recommendations to the filmmakers cinematic techniques are offered by Stereo D at each step from pre-production onwards, through set, into post. As the footage arrives at our facility we respond in depth to the cinematic qualities of the imagery in context of the edit and story, with the guidance of the Directors and Studio, creating stereoscopic imagery. Our involvement in The Avengers was early in production, after reading the script we had the opportunity and honor to meet and work with the Director Joss Whedon, and DP Seamus McGarvey on set, and into post. We presented what is obvious to such great filmmakers in the ways of cinematic techniques as they related to the standard depth cues and story points we would use to evaluate depth for their film. Our hope was any cinematic habits that supported better 3D would be emphasized. In searching for a 3D statement for the studio and filmmakers we arrived at a stereographic style that allowed for comfort and maximum visual engagement to the viewer.

  6. Studies of the 3D surface roughness height

    SciTech Connect

    Avisane, Anita; Rudzitis, Janis; Kumermanis, Maris

    2013-12-16

    Nowadays nano-coatings occupy more and more significant place in technology. Innovative, functional coatings acquire new aspects from the point of view of modern technologies, considering the aggregate of physical properties that can be achieved manipulating in the production process with the properties of coatings’ surfaces on micro- and nano-level. Nano-coatings are applied on machine parts, friction surfaces, contacting parts, corrosion surfaces, transparent conducting films (TCF), etc. The equipment available at present for the production of transparent conducting oxide (TCO) coatings with highest quality is based on expensive indium tin oxide (ITO) material; therefore cheaper alternatives are being searched for. One such offered alternative is zink oxide (ZnO) nano-coatings. Evaluating the TCF physical and mechanical properties and in view of the new ISO standard (EN ISO 25178) on the introduction of surface texture (3D surface roughness) in the engineering calculations, it is necessary to examine the height of 3D surface roughness, which is one of the most significant roughness parameters. The given paper studies the average values of 3D surface roughness height and the most often applied distribution laws are as follows: the normal distribution and Rayleigh distribution. The 3D surface is simulated by a normal random field.

  7. Numerical study on 3D composite morphing actuators

    NASA Astrophysics Data System (ADS)

    Oishi, Kazuma; Saito, Makoto; Anandan, Nishita; Kadooka, Kevin; Taya, Minoru

    2015-04-01

    There are a number of actuators using the deformation of electroactive polymer (EAP), where fewer papers seem to have focused on the performance of 3D morphing actuators based on the analytical approach, due mainly to their complexity. The present paper introduces a numerical analysis approach on the large scale deformation and motion of a 3D half dome shaped actuator composed of thin soft membrane (passive material) and EAP strip actuators (EAP active coupon with electrodes on both surfaces), where the locations of the active EAP strips is a key parameter. Simulia/Abaqus Static and Implicit analysis code, whose main feature is the high precision contact analysis capability among structures, are used focusing on the whole process of the membrane to touch and wrap around the object. The unidirectional properties of the EAP coupon actuator are used as input data set for the material properties for the simulation and the verification of our numerical model, where the verification is made as compared to the existing 2D solution. The numerical results can demonstrate the whole deformation process of the membrane to wrap around not only smooth shaped objects like a sphere or an egg, but also irregularly shaped objects. A parametric study reveals the proper placement of the EAP coupon actuators, with the modification of the dome shape to induce the relevant large scale deformation. The numerical simulation for the 3D soft actuators shown in this paper could be applied to a wider range of soft 3D morphing actuators.

  8. AQUATIC TOXICITY MODE OF ACTION STUDIES APPLIED TO QSAR DEVELOPMENT

    EPA Science Inventory

    A series of QSAR models for predicting fish acute lethality were developed using systematically collected data on more than 600 chemicals. These models were developed based on the assumption that chemicals producing toxicity through a common mechanism will have commonality in the...

  9. 3D Regression Heat Map Analysis of Population Study Data.

    PubMed

    Klemm, Paul; Lawonn, Kai; Glaßer, Sylvia; Niemann, Uli; Hegenscheid, Katrin; Völzke, Henry; Preim, Bernhard

    2016-01-01

    Epidemiological studies comprise heterogeneous data about a subject group to define disease-specific risk factors. These data contain information (features) about a subject's lifestyle, medical status as well as medical image data. Statistical regression analysis is used to evaluate these features and to identify feature combinations indicating a disease (the target feature). We propose an analysis approach of epidemiological data sets by incorporating all features in an exhaustive regression-based analysis. This approach combines all independent features w.r.t. a target feature. It provides a visualization that reveals insights into the data by highlighting relationships. The 3D Regression Heat Map, a novel 3D visual encoding, acts as an overview of the whole data set. It shows all combinations of two to three independent features with a specific target disease. Slicing through the 3D Regression Heat Map allows for the detailed analysis of the underlying relationships. Expert knowledge about disease-specific hypotheses can be included into the analysis by adjusting the regression model formulas. Furthermore, the influences of features can be assessed using a difference view comparing different calculation results. We applied our 3D Regression Heat Map method to a hepatic steatosis data set to reproduce results from a data mining-driven analysis. A qualitative analysis was conducted on a breast density data set. We were able to derive new hypotheses about relations between breast density and breast lesions with breast cancer. With the 3D Regression Heat Map, we present a visual overview of epidemiological data that allows for the first time an interactive regression-based analysis of large feature sets with respect to a disease.

  10. In silico study of in vitro GPCR assays by QSAR modeling ...

    EPA Pesticide Factsheets

    The U.S. EPA is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays (the ToxCast program). One goal is to prioritize chemicals for more detailed analyses based on activity in molecular initiating events (MIE) of adverse outcome pathways (AOPs). However, the chemical space of interest for environmental exposure is much wider than this set of chemicals. Thus, there is a need to fill data gaps with in silico methods, and quantitative structure-activity relationships (QSARs) are a proven and cost effective approach to predict biological activity. ToxCast in turn provides relatively large datasets that are ideal for training and testing QSAR models. The overall goal of the study described here was to develop QSAR models to fill the data gaps in a larger environmental database of ~32k structures. The specific aim of the current work was to build QSAR models for 18 G-Protein Coupled Receptor (GPCR) assays, part of the aminergic category. Two QSAR modeling strategies were adopted: classification models were developed to separate chemicals into active/non-active classes, and then regression models were built to predict the potency values of the bioassays for the active chemicals. Multiple software programs were used to calculate constitutional, topological and substructural molecular descriptors from two-dimensional (2D) chemical structures. Model-fitting methods included PLSDA (partial least squares d

  11. Method and simulation to study 3D crosstalk perception

    NASA Astrophysics Data System (ADS)

    Khaustova, Dar'ya; Blondé, Laurent; Huynh-Thu, Quan; Vienne, Cyril; Doyen, Didier

    2012-03-01

    To various degrees, all modern 3DTV displays suffer from crosstalk, which can lead to a decrease of both visual quality and visual comfort, and also affect perception of depth. In the absence of a perfect 3D display technology, crosstalk has to be taken into account when studying perception of 3D stereoscopic content. In order to improve 3D presentation systems and understand how to efficiently eliminate crosstalk, it is necessary to understand its impact on human perception. In this paper, we present a practical method to study the perception of crosstalk. The approach consists of four steps: (1) physical measurements of a 3DTV, (2) building of a crosstalk surface based on those measurements and representing specifically the behavior of that 3TV, (3) manipulation of the crosstalk function and application on reference images to produce test images degraded by crosstalk in various ways, and (4) psychophysical tests. Our approach allows both a realistic representation of the behavior of a 3DTV and the easy manipulation of its resulting crosstalk in order to conduct psycho-visual experiments. Our approach can be used in all studies requiring the understanding of how crosstalk affects perception of stereoscopic content and how it can be corrected efficiently.

  12. Surface topography study of prepared 3D printed moulds via 3D printer for silicone elastomer based nasal prosthesis

    NASA Astrophysics Data System (ADS)

    Abdullah, Abdul Manaf; Din, Tengku Noor Daimah Tengku; Mohamad, Dasmawati; Rahim, Tuan Noraihan Azila Tuan; Akil, Hazizan Md; Rajion, Zainul Ahmad

    2016-12-01

    Conventional prosthesis fabrication is highly depends on the hand creativity of laboratory technologist. The development in 3D printing technology offers a great help in fabricating affordable and fast yet esthetically acceptable prostheses. This study was conducted to discover the potential of 3D printed moulds for indirect silicone elastomer based nasal prosthesis fabrication. Moulds were designed using computer aided design (CAD) software (Solidworks, USA) and converted into the standard tessellation language (STL) file. Three moulds with layer thickness of 0.1, 0.2 and 0.3mm were printed utilizing polymer filament based 3D printer (Makerbot Replicator 2X, Makerbot, USA). Another one mould was printed utilizing liquid resin based 3D printer (Objet 30 Scholar, Stratasys, USA) as control. The printed moulds were then used to fabricate maxillofacial silicone specimens (n=10)/mould. Surface profilometer (Surfcom Flex, Accretech, Japan), digital microscope (KH77000, Hirox, USA) and scanning electron microscope (Quanta FEG 450, Fei, USA) were used to measure the surface roughness as well as the topological properties of fabricated silicone. Statistical analysis of One-Way ANOVA was employed to compare the surface roughness of the fabricated silicone elastomer. Result obtained demonstrated significant differences in surface roughness of the fabricated silicone (p<0.01). Further post hoc analysis also revealed significant differences in silicone fabricated using different 3D printed moulds (p<0.01). A 3D printed mould was successfully prepared and characterized. With surface topography that could be enhanced, inexpensive and rapid mould fabrication techniques, polymer filament based 3D printer is potential for indirect silicone elastomer based nasal prosthesis fabrication.

  13. 3D ultrasound computer tomography: update from a clinical study

    NASA Astrophysics Data System (ADS)

    Hopp, T.; Zapf, M.; Kretzek, E.; Henrich, J.; Tukalo, A.; Gemmeke, H.; Kaiser, C.; Knaudt, J.; Ruiter, N. V.

    2016-04-01

    Ultrasound Computer Tomography (USCT) is a promising new imaging method for breast cancer diagnosis. We developed a 3D USCT system and tested it in a pilot study with encouraging results: 3D USCT was able to depict two carcinomas, which were present in contrast enhanced MRI volumes serving as ground truth. To overcome severe differences in the breast shape, an image registration was applied. We analyzed the correlation between average sound speed in the breast and the breast density estimated from segmented MRIs and found a positive correlation with R=0.70. Based on the results of the pilot study we now carry out a successive clinical study with 200 patients. For this we integrated our reconstruction methods and image post-processing into a comprehensive workflow. It includes a dedicated DICOM viewer for interactive assessment of fused USCT images. A new preview mode now allows intuitive and faster patient positioning. We updated the USCT system to decrease the data acquisition time by approximately factor two and to increase the penetration depth of the breast into the USCT aperture by 1 cm. Furthermore the compute-intensive reflectivity reconstruction was considerably accelerated, now allowing a sub-millimeter volume reconstruction in approximately 16 minutes. The updates made it possible to successfully image first patients in our ongoing clinical study.

  14. Controlled architectural and chemotactic studies of 3D cell migration.

    PubMed

    Tayalia, Prakriti; Mazur, Eric; Mooney, David J

    2011-04-01

    Chemotaxis plays a critical role in tissue development and wound repair, and is widely studied using ex vivo model systems in applications such as immunotherapy. However, typical chemotactic models employ 2D systems that are less physiologically relevant or use end-point assays, that reveal little about the stepwise dynamics of the migration process. To overcome these limitations, we developed a new model system using microfabrication techniques, sustained drug delivery approaches, and theoretical modeling of chemotactic agent diffusion. This model system allows us to study the effects of 3D architecture and chemotactic agent gradient on immune cell migration in real time. We find that dendritic cell migration is characterized by a strong interplay between matrix architecture and chemotactic gradients, and migration is also influenced dramatically by the cell activation state. Our results indicate that Lipopolysaccharide-activated dendritic cells studied in a traditional transwell system actually exhibit anomalous migration behavior. Such a 3D ex vivo system lends itself for analyzing cell migratory behavior in response to single or multiple competitive cues and could prove useful in vaccine development.

  15. Nonlinear 3D MHD verification study: SpeCyl and PIXIE3D codes for RFP and Tokamak plasmas

    NASA Astrophysics Data System (ADS)

    Bonfiglio, D.; Cappello, S.; Chacon, L.

    2010-11-01

    A strong emphasis is presently placed in the fusion community on reaching predictive capability of computational models. An essential requirement of such endeavor is the process of assessing the mathematical correctness of computational tools, termed verification [1]. We present here a successful nonlinear cross-benchmark verification study between the 3D nonlinear MHD codes SpeCyl [2] and PIXIE3D [3]. Excellent quantitative agreement is obtained in both 2D and 3D nonlinear visco-resistive dynamics for reversed-field pinch (RFP) and tokamak configurations [4]. RFP dynamics, in particular, lends itself as an ideal non trivial test-bed for 3D nonlinear verification. Perspectives for future application of the fully-implicit parallel code PIXIE3D to RFP physics, in particular to address open issues on RFP helical self-organization, will be provided. [4pt] [1] M. Greenwald, Phys. Plasmas 17, 058101 (2010) [0pt] [2] S. Cappello and D. Biskamp, Nucl. Fusion 36, 571 (1996) [0pt] [3] L. Chac'on, Phys. Plasmas 15, 056103 (2008) [0pt] [4] D. Bonfiglio, L. Chac'on and S. Cappello, Phys. Plasmas 17 (2010)

  16. QSAR study of selective ligands for the thyroid hormone receptor beta.

    PubMed

    Liu, Huanxiang; Gramatica, Paola

    2007-08-01

    In this paper, an accurate and reliable QSAR model of 87 selective ligands for the thyroid hormone receptor beta 1 (TRbeta1) was developed, based on theoretical molecular descriptors to predict the binding affinity of compounds with receptor. The structural characteristics of compounds were described wholly by a large amount of molecular structural descriptors calculated by DRAGON. Six most relevant structural descriptors to the studied activity were selected as the inputs of QSAR model by a robust optimization algorithm Genetic Algorithm. The built model was fully assessed by various validation methods, including internal and external validation, Y-randomization test, chemical applicability domain, and all the validations indicate that the QSAR model we proposed is robust and satisfactory. Thus, the built QSAR model can be used to fast and accurately predict the binding affinity of compounds (in the defined applicability domain) to TRbeta1. At the same time, the model proposed could also identify and provide some insight into what structural features are related to the biological activity of these compounds and provide some instruction for further designing the new selective ligands for TRbeta1 with high activity.

  17. The effects of characteristics of substituents on toxicity of the nitroaromatics: HiT QSAR study

    NASA Astrophysics Data System (ADS)

    Kuz'min, Victor E.; Muratov, Eugene N.; Artemenko, Anatoly G.; Gorb, Leonid; Qasim, Mohammad; Leszczynski, Jerzy

    2008-10-01

    The present study applies the Hierarchical Technology for Quantitative Structure-Activity Relationships (HiT QSAR) for (i) evaluation of the influence of the characteristics of 28 nitroaromatic compounds (some of which belong to a widely known class of explosives) as to their toxicity; (ii) prediction of toxicity for new nitroaromatic derivatives; (iii) analysis of the effects of substituents in nitroaromatic compounds on their toxicity in vivo. The 50% lethal dose concentration for rats (LD50) was used to develop the QSAR models based on simplex representation of molecular structure. The preliminary 1D QSAR results show that even the information on the composition of molecules reveals the main tendencies of changes in toxicity. The statistic characteristics for partial least squares 2D QSAR models are quite satisfactory ( R 2 = 0.96-0.98; Q 2 = 0.91-0.93; R 2 test = 0.89-0.92), which allows us to carry out the prediction of activity for 41 novel compounds designed by the application of new combinations of substituents represented in the training set. The comprehensive analysis of toxicity changes as a function of substituent position and nature was carried out. Molecular fragments that promote and interfere with toxicity were defined on the basis of the obtained models. It was shown that the mutual influence of substituents in the benzene ring plays a crucial role regarding toxicity. The influence of different substituents on toxicity can be mediated via different C-H fragments of the aromatic ring.

  18. Evaluation of 3-D graphics software: A case study

    NASA Technical Reports Server (NTRS)

    Lores, M. E.; Chasen, S. H.; Garner, J. M.

    1984-01-01

    An efficient 3-D geometry graphics software package which is suitable for advanced design studies was developed. The advanced design system is called GRADE--Graphics for Advanced Design. Efficiency and ease of use are gained by sacrificing flexibility in surface representation. The immediate options were either to continue development of GRADE or to acquire a commercially available system which would replace or complement GRADE. Test cases which would reveal the ability of each system to satisfy the requirements were developed. A scoring method which adequately captured the relative capabilities of the three systems was presented. While more complex multi-attribute decision methods could be used, the selected method provides all the needed information without being so complex that it is difficult to understand. If the value factors are modestly perturbed, system Z is a clear winner based on its overall capabilities. System Z is superior in two vital areas: surfacing and ease of interface with application programs.

  19. Improved Surgery Planning Using 3-D Printing: a Case Study.

    PubMed

    Singhal, A J; Shetty, V; Bhagavan, K R; Ragothaman, Ananthan; Shetty, V; Koneru, Ganesh; Agarwala, M

    2016-04-01

    The role of 3-D printing is presented for improved patient-specific surgery planning. Key benefits are time saved and surgery outcome. Two hard-tissue surgery models were 3-D printed, for orthopedic, pelvic surgery, and craniofacial surgery. We discuss software data conversion in computed tomography (CT)/magnetic resonance (MR) medical image for 3-D printing. 3-D printed models save time in surgery planning and help visualize complex pre-operative anatomy. Time saved in surgery planning can be as much as two thirds. In addition to improved surgery accuracy, 3-D printing presents opportunity in materials research. Other hard-tissue and soft-tissue cases in maxillofacial, abdominal, thoracic, cardiac, orthodontics, and neurosurgery are considered. We recommend using 3-D printing as standard protocol for surgery planning and for teaching surgery practices. A quick turnaround time of a 3-D printed surgery model, in improved accuracy in surgery planning, is helpful for the surgery team. It is recommended that these costs be within 20 % of the total surgery budget.

  20. Elemental concentration distribution in human fingernails - A 3D study

    NASA Astrophysics Data System (ADS)

    Pineda-Vargas, C. A.; Mars, J. A.; Gihwala, D.

    2012-02-01

    The verification of pathologies has normally been based on analysis of blood (serum and plasma), and physiological tissue. Recently, nails and in particular human fingernails have become an important medium for pathological studies, especially those of environmental origin. The analytical technique of PIXE has been used extensively in the analysis of industrial samples and human tissue specimens. The application of the analytical technique to nails has been mainly to bulk samples. In this study we use micro-PIXE and -RBS, as both complementary and supplementary, to determine the elemental concentration distribution of human fingernails of individuals. We report on the 3D quantitative elemental concentration distributions (QECDs) of various elements that include C, N and O as major elements (10-20%), P, S, Cl, K and Ca as minor elements (1-10%) and Fe, Mn, Zn, Ti, Na, Mg, Cu, Ni, Cr, Rb, Br, Sr and Se as trace elements (less than 1%). For PIXE and RBS the specimens were bombarded with a 3 MeV proton beam. To ascertain any correlations in the quantitative elemental concentration distributions, a linear traverse analysis was performed across the width of the nail. Elemental distribution correlations were also obtained.

  1. A review of QSAR studies to discover new drug-like compounds actives against leishmaniasis and trypanosomiasis.

    PubMed

    Castillo-Garit, Juan Alberto; Abad, Concepción; Rodríguez-Borges, J Enrique; Marrero-Ponce, Yovani; Torrens, Francisco

    2012-01-01

    The neglected tropical diseases (NTDs) affect more than one billion people (one-sixth of the world's population) and occur primarily in undeveloped countries in sub-Saharan Africa, Asia, and Latin America. Available drugs for these diseases are decades old and present an important number of limitations, especially high toxicity and, more recently, the emergence of drug resistance. In the last decade several Quantitative Structure-Activity Relationship (QSAR) studies have been developed in order to identify new organic compounds with activity against the parasites responsible for these diseases, which are reviewed in this paper. The topics summarized in this work are: 1) QSAR studies to identify new organic compounds actives against Chaga's disease; 2) Development of QSAR studies to discover new antileishmanial drusg; 3) Computational studies to identify new drug-like compounds against human African trypanosomiasis. Each topic include the general characteristics, epidemiology and chemotherapy of the disease as well as the main QSAR approaches to discovery/identification of new actives compounds for the corresponding neglected disease. The last section is devoted to a new approach know as multi-target QSAR models developed for antiparasitic drugs specifically those actives against trypanosomatid parasites. At present, as a result of these QSAR studies several promising compounds, active against these parasites, are been indentify. However, more efforts will be required in the future to develop more selective (specific) useful drugs.

  2. Quantitative structure-activity relationship (QSAR) study of a series of benzimidazole derivatives as inhibitors of Saccharomyces cerevisiae.

    PubMed

    Podunavac-Kuzmanović, Sonja O; Cvetković, Dragoljub D; Jevrić, Lidija R; Uzelac, Natasa J

    2013-01-01

    A quantitative structure activity relationship (QSAR) has been carried out on a series of benzimidazole derivatives to identify the structural requirements for their inhibitory activity against yeast Saccharomyces cerevisiae. A multiple linear regression (MLR) procedure was used to model the relationships between various physicochemical, steric, electronic, and structural molecular descriptors and antifungal activity of benzimidazole derivatives. The QSAR expressions were generated using a training set of 16 compounds and the predictive ability of the resulting models was evaluated against a test set of 8 compounds. The best QSAR models were further validated by leave one out technique as well as by the calculation of statistical parameters for the established theoretical models. Therefore, satisfactory relationships between antifungal activity and molecular descriptors were found. QSAR analysis reveals that lipophilicity descriptor (logP), dipole moment (DM) and surface area grid (SAG) govern the inhibitory activity of compounds studied against Saccharomyces cerevisiae.

  3. Application of 3D printing technology in aerodynamic study

    NASA Astrophysics Data System (ADS)

    Olasek, K.; Wiklak, P.

    2014-08-01

    3D printing, as an additive process, offers much more than traditional machining techniques in terms of achievable complexity of a model shape. That fact was a motivation to adapt discussed technology as a method for creating objects purposed for aerodynamic testing. The following paper provides an overview of various 3D printing techniques. Four models of a standard NACA0018 aerofoil were manufactured in different materials and methods: MultiJet Modelling (MJM), Selective Laser Sintering (SLS) and Fused Deposition Modeling (FDM). Various parameters of the models have been included in the analysis: surface roughness, strength, details quality, surface imperfections and irregularities as well as thermal properties.

  4. Anilides and quinolones with nitrogen-bearing substituents from benzothiophene and thienothiophene series: synthesis, photochemical synthesis, cytostatic evaluation, 3D-derived QSAR analysis and DNA-binding properties.

    PubMed

    Aleksić, Maja; Bertoša, Branimir; Nhili, Raja; Depauw, Sabine; Martin-Kleiner, Irena; David-Cordonnier, Marie-Hélène; Tomić, Sanja; Kralj, Marijeta; Karminski-Zamola, Grace

    2014-01-01

    A series of new anilides (2a-c, 4-7, 17a-c, 18) and quinolones (3a-b, 8a-b, 9a-b, 10-15, 19) with nitrogen-bearing substituents from benzo[b]thiophene and thieno[2,3-c]thiophene series are prepared. Benzo[b]thieno[2,3-c]- and thieno[3',2':4,5]thieno[2,3-c]quinolones (3a-b, 8a-b) are synthesized by the reaction of photochemical dehydrohalogenation from corresponding anilides. Anilides and quinolones were tested for the antiproliferative activity. Fused quinolones bearing protonated aminium group, quaternary ammonium group, N-methylated and protonated aminium group, amino and protonated amino group (8a, 9b, 10-12) showed very prominent anticancer activity, whereby the hydrochloride salt of N',N'-dimethylaminopropyl-substituted quinolone (14) was the most active one, having the IC50 concentration at submicromolar range in accordance with previous QSAR predictions. On the other hand, flexible anilides were among the less active. Chemometric analysis of investigated compounds was performed. 3D-derived QSAR analysis identified solubility, metabolitic stability and the possibility of the compound to be ionized at pH 4-8 as molecular properties that are positively correlated with anticancer activity of investigated compounds, while molecular flexibility, polarizability and sum of hydrophobic surface areas were found to be negatively correlated. Anilides 2a-b, 4-7 and quinolones 3a-b, 8a-b, 9b and 10-14 were evaluated for DNA binding propensities and topoisomerases I/II inhibition as part of their mechanism of action. Among the anilides, only compound 7 presented some DNA binding propensity whereas the quinolones 8b, 9b and 10-14 intercalate in the DNA base pairs, compounds 8b, 9b and 14 being the most efficient ones. The strongest DNA intercalators, compounds 8b, 9b and 14, were clearly distinguished from the other compounds according to their molecular descriptors by the PCA and PLS analysis.

  5. Assessment of 3D Models Used in Contours Studies

    ERIC Educational Resources Information Center

    Alvarez, F. J. Ayala; Parra, E. B. Blazquez; Tubio, F. Montes

    2015-01-01

    This paper presents an experimental research focusing on the view of first year students. The aim is to check the quality of implementing 3D models integrated in the curriculum. We search to determine students' preference between the various means facilitated in order to understand the given subject. Students have been respondents to prove the…

  6. A 3D measurement of the offset in paleoseismological studies

    NASA Astrophysics Data System (ADS)

    Ferrater, Marta; Echeverria, Anna; Masana, Eulàlia; Martínez-Díaz, José J.; Sharp, Warren D.

    2016-05-01

    The slip rate of a seismogenic fault is a crucial parameter for establishing the contribution of the fault to the seismic hazard. It is calculated from measurements of the offset of linear landforms, such channels, produced by the fault combined with their age. The three-dimensional measurement of offset in buried paleochannels is subject to uncertainties that need to be quantitatively assessed and propagated into the slip rate. Here, we present a set of adapted scripts to calculate the net, lateral and vertical tectonic offset components caused by faults, together with their associated uncertainties. This technique is applied here to a buried channel identified in the stratigraphic record during a paleoseismological study at the El Saltador site (Alhama de Murcia fault, Iberian Peninsula). After defining and measuring the coordinates of the key points of a buried channel in the walls of eight trenches excavated parallel to the fault, we (a) adjusted a 3D straight line to these points and then extrapolated the tendency of this line onto a simplified fault plane; (b) repeated these two steps for the segment of the channel in the other side of the fault; and (c) measured the distance between the two resulting intersection points with the fault plane. In doing so, we avoided the near fault modification of the channel trace and obtained a three-dimensional measurement of offset and its uncertainty. This methodology is a substantial modification of previous procedures that require excavating progressively towards the fault, leading to possible underestimation of offset due to diffuse deformation near the fault. Combining the offset with numerical dating of the buried channel via U-series on soil carbonate, we calculated a maximum estimate of the net slip rate and its vertical and lateral components for the Alhama de Murcia fault.

  7. Study, simulation and design of a 3D clinostat

    NASA Astrophysics Data System (ADS)

    Pavone, Valentina; Guarnieri, Vincenzo; Lobascio, Cesare; Soma, Aurelio; Bosso, Nicola; Lamantea, Matteo Maria

    High cost and limited number of physically executable experiments in space have introduced the need for ground simulation systems that enable preparing experiments to be carried out on board, identifying phenomena associated with the altered gravity conditions, and taking advantage of these conditions, as in Biotechnology. Among systems developed to simulate microgravity, especially for life sciences experiments, different types of clinostats were realized. This work deals with mechanical design of a three-dimensional clinostat and simulation of the dynamic behavior of the system by varying the operating parameters. The design and simulation phase was preceded by a careful analysis of the state of art and by the review of the most recent results, in particular from the major investigators of Life Sciences in Space. The mechanical design is quite innovative by adoption of a structure entirely in aluminum, which allows robustness while reducing the overall weight. The transmission system of motion has been optimized by means of brushless DC micro motors, light and compact, which helped to reduce weight, dimensions, power consumption and increase the reliability and durability of the system. The study of the dynamic behavior using SIMPACK, a multibody simulation software, led to results in line with those found in the most important and recent scientific publications. This model was also appropriately configured to represent any desired operating condition, and for eventual system scalability. It would be interesting to generate simulated hypogravity - e.g.: 0.38-g (Mars) or 0.17-g (Moon). This would allow to investigate how terrestrial life forms can grow in other planetary habitats, or to determine the gravity threshold response of different organisms. At the moment, such a system can only be achieved by centrifuges in real microgravity. We are confident that simulation and associated tests with our 3D clinostat can help adjusting the parameters allowing variable g

  8. Towards understanding mechanisms governing cytotoxicity of metal oxides nanoparticles: hints from nano-QSAR studies.

    PubMed

    Gajewicz, Agnieszka; Schaeublin, Nicole; Rasulev, Bakhtiyor; Hussain, Saber; Leszczynska, Danuta; Puzyn, Tomasz; Leszczynski, Jerzy

    2015-05-01

    The production of nanomaterials increases every year exponentially and therefore the probability these novel materials that they could cause adverse outcomes for human health and the environment also expands rapidly. We proposed two types of mechanisms of toxic action that are collectively applied in a nano-QSAR model, which provides governance over the toxicity of metal oxide nanoparticles to the human keratinocyte cell line (HaCaT). The combined experimental-theoretical studies allowed the development of an interpretative nano-QSAR model describing the toxicity of 18 nano-metal oxides to the HaCaT cell line, which is a common in vitro model for keratinocyte response during toxic dermal exposure. The comparison of the toxicity of metal oxide nanoparticles to bacteria Escherichia coli (prokaryotic system) and a human keratinocyte cell line (eukaryotic system), resulted in the hypothesis that different modes of toxic action occur between prokaryotic and eukaryotic systems.

  9. OB3D, a new set of 3D objects available for research: a web-based study

    PubMed Central

    Buffat, Stéphane; Chastres, Véronique; Bichot, Alain; Rider, Delphine; Benmussa, Frédéric; Lorenceau, Jean

    2014-01-01

    Studying object recognition is central to fundamental and clinical research on cognitive functions but suffers from the limitations of the available sets that cannot always be modified and adapted to meet the specific goals of each study. We here present a new set of 3D scans of real objects available on-line as ASCII files, OB3D. These files are lists of dots, each defined by a triplet of spatial coordinates and their normal that allow simple and highly versatile transformations and adaptations. We performed a web-based experiment to evaluate the minimal number of dots required for the denomination and categorization of these objects, thus providing a reference threshold. We further analyze several other variables derived from this data set, such as the correlations with object complexity. This new stimulus set, which was found to activate the Lower Occipital Complex (LOC) in another study, may be of interest for studies of cognitive functions in healthy participants and patients with cognitive impairments, including visual perception, language, memory, etc. PMID:25339920

  10. Evaluation of the EVA descriptor for QSAR studies: 3. The use of a genetic algorithm to search for models with enhanced predictive properties (EVA_GA)

    NASA Astrophysics Data System (ADS)

    Turner, David B.; Willett, Peter

    2000-01-01

    The EVA structural descriptor, based upon calculated fundamental molecular vibrational frequencies, has proved to be an effective descriptor for both QSAR and database similarity calculations. The descriptor is sensitive to 3D structure but has an advantage over field-based 3D-QSAR methods inasmuch as structural superposition is not required. The original technique involves a standardisation method wherein uniform Gaussians of fixed standard deviation (σ) are used to smear out frequencies projected onto a linear scale. The smearing function permits the overlap of proximal frequencies and thence the extraction of a fixed dimensional descriptor regardless of the number and precise values of the frequencies. It is proposed here that there exist optimal localised values of σ in different spectral regions; that is, the overlap of frequencies using uniform Gaussians may, at certain points in the spectrum, either be insufficient to pick up relationships where they exist or mix up information to such an extent that significant correlations are obscured by noise. A genetic algorithm is used to search for optimal localised σ values using crossvalidated PLS regression scores as the fitness score to be optimised. The resultant models were then validated against a previously unseen test set of compounds and through data scrambling. The performance of EVA_GA is compared to that of EVA and analogous CoMFA studies; in the latter case a brief evaluation is made of the effect of grid resolution upon the stability of CoMFA PLS scores particularly in relation to test set predictions.

  11. On 3D Dimension: Study cases for Archaeological sites

    NASA Astrophysics Data System (ADS)

    D'Urso, M. G.; Marino, C. L.; Rotondi, A.

    2014-04-01

    For more than a century the tridimensional vision has been of interest for scientists and users in several fields of application. The mathematical bases have remained substantially unchanged but only the new technologies have allowed us to make the vision really impressive. Photography opens new frontiers and has enriched of physical, mathematical, chemical, informatical and topographic notions by making the images so real to make the observer fully immersed into the represented scene. By means of active googless the 3D digital technique, commonly used for video games, makes possible animations without limitations in the dimension of the images thanks to the improved performances of the graphic processor units and related hardware components. In this paper we illustrate an experience made by the students of the MSc'degree course of Topography, active at the University of Cassino and Southern Lazio, in which the photography has been applied as an innovative technique for the surveying of cultural heritage. The tests foresee the use of traditional techniques of survey with 3D digital images and use of GPS sensors. The ultimate objective of our experience is the insertion in the web, allowing us the visualization of the 3D images equipped with all data. In conclusion these new methods of survey allow for the fusion of extremely different techniques, in such an impressive way to make them inseparable and justifying the origin of the neologism "Geomatics" coined at the Laval University (Canada) during the eighties.

  12. Towards global QSAR model building for acute toxicity: Munro database case study.

    PubMed

    Chavan, Swapnil; Nicholls, Ian A; Karlsson, Björn C G; Rosengren, Annika M; Ballabio, Davide; Consonni, Viviana; Todeschini, Roberto

    2014-10-09

    A series of 436 Munro database chemicals were studied with respect to their corresponding experimental LD50 values to investigate the possibility of establishing a global QSAR model for acute toxicity. Dragon molecular descriptors were used for the QSAR model development and genetic algorithms were used to select descriptors better correlated with toxicity data. Toxic values were discretized in a qualitative class on the basis of the Globally Harmonized Scheme: the 436 chemicals were divided into 3 classes based on their experimental LD50 values: highly toxic, intermediate toxic and low to non-toxic. The k-nearest neighbor (k-NN) classification method was calibrated on 25 molecular descriptors and gave a non-error rate (NER) equal to 0.66 and 0.57 for internal and external prediction sets, respectively. Even if the classification performances are not optimal, the subsequent analysis of the selected descriptors and their relationship with toxicity levels constitute a step towards the development of a global QSAR model for acute toxicity.

  13. QSAR studies, synthesis and antibacterial assessment of new inhibitors against multidrug-resistant Mycobacterium tuberculosis.

    PubMed

    Kovalishyn, Vasyl; Brovarets, Volodymyr; Blagodatnyi, Volodymyr; Kopernyk, Iryna; Hodyna, Diana; Chumachenko, Svitlana; Shablykin, Oleg; Kozachenko, Oleksandr; Vovk, Myhailo; Barus, Marianna; Bratenko, Myhailo; Metelytsia, Larysa

    2016-11-08

    This paper describes Quantitative Structure-Activity Relationships (QSAR) studies using Artificial Neural Networks (ANN), synthesis and in vitro antitubercular activity of several potent compounds against H37Rv and resistant Mycobacterium tuberculosis (Mtb) strains. Eight QSAR models were built using various types of descriptors with four publicly available structurally diverse datasets, including recent data from PubChem and ChEMBL. The predictive power of the obtained QSAR models was evaluated with a cross-validation procedure, giving a q2=0.74-0.78 for regression models and overall accuracy 78.9-94.4% for classification models. The external test sets were predicted with accuracies in the range of 84.1-95.0% (for the active/inactive classifications) and q2=0.80-0.83 for regressions. The 15 synthesized compounds showed inhibitory activity against H37Rv strain whereas the compounds 1-7 were also active against resistant Mtb strain (resistant to isoniazid and rifampicin). The results indicated that compounds 1-7 could serve as promising leads for further optimization as novel antibacterial inhibitors, in particular, for the treatment of drug resistance of Mtb forms.

  14. Unified QSAR approach to antimicrobials. 4. Multi-target QSAR modeling and comparative multi-distance study of the giant components of antiviral drug-drug complex networks.

    PubMed

    Prado-Prado, Francisco J; Martinez de la Vega, Octavio; Uriarte, Eugenio; Ubeira, Florencio M; Chou, Kuo-Chen; González-Díaz, Humberto

    2009-01-15

    One limitation of almost all antiviral Quantitative Structure-Activity Relationships (QSAR) models is that they predict the biological activity of drugs against only one species of virus. Consequently, the development of multi-tasking QSAR models (mt-QSAR) to predict drugs activity against different species of virus is of the major vitally important. These mt-QSARs offer also a good opportunity to construct drug-drug Complex Networks (CNs) that can be used to explore large and complex drug-viral species databases. It is known that in very large CNs we can use the Giant Component (GC) as a representative sub-set of nodes (drugs) and but the drug-drug similarity function selected may strongly determines the final network obtained. In the three previous works of the present series we reported mt-QSAR models to predict the antimicrobial activity against different fungi [Gonzalez-Diaz, H.; Prado-Prado, F. J.; Santana, L.; Uriarte, E. Bioorg.Med.Chem.2006, 14, 5973], bacteria [Prado-Prado, F. J.; Gonzalez-Diaz, H.; Santana, L.; Uriarte E. Bioorg.Med.Chem.2007, 15, 897] or parasite species [Prado-Prado, F.J.; González-Díaz, H.; Martinez de la Vega, O.; Ubeira, F.M.; Chou K.C. Bioorg.Med.Chem.2008, 16, 5871]. However, including these works, we do not found any report of mt-QSAR models for antivirals drug, or a comparative study of the different GC extracted from drug-drug CNs based on different similarity functions. In this work, we used Linear Discriminant Analysis (LDA) to fit a mt-QSAR model that classify 600 drugs as active or non-active against the 41 different tested species of virus. The model correctly classifies 143 of 169 active compounds (specificity=84.62%) and 119 of 139 non-active compounds (sensitivity=85.61%) and presents overall training accuracy of 85.1% (262 of 308 cases). Validation of the model was carried out by means of external predicting series, classifying the model 466 of 514, 90.7% of compounds. In order to illustrate the performance of the

  15. 3D tomodosimetry using long scintillating fibers: A feasibility study

    SciTech Connect

    Goulet, Mathieu; Archambault, Louis; Beaulieu, Luc; Gingras, Luc

    2013-10-15

    Purpose: 3D dosimetry is recognized as an ideal for patient-specific quality assurance (QA) of highly conformal radiotherapy treatments. However, existing 3D dosimeters are not straightforward to implement in the clinic, as their read-out procedure is often tedious and their accuracy, precision, and/or sample size exhibit limitations. The purpose of this work is to develop a 3D dosimeter based on the concept of tomodosimetry inside concentric cylindrical planes using long scintillating fibers for the QA of modern radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) or intensity-modulated arc therapy (IMAT).Methods: Using a model-based simulation, scintillating fibers were modeled on three concentric cylindrical planes of radii 2.5, 5.0, and 7.5 cm, inside a 10 cm radius water-equivalent cylinder phantom. The phantom was set to rotate around its central axis, made parallel to the linac gantry axis of rotation. Light acquisitions were simulated using the calculated dose from the treatment planning software and reconstructed in each cylindrical plane at a resolution of 1 mm{sup 2} using a total-variation minimization iterative reconstruction algorithm. The 3D dose was then interpolated from the reconstructed cylindrical plane doses at a resolution of 1 mm{sup 3}. Different scintillating fiber patterns were compared by varying the angle of each fiber in its cylindrical plane and introducing a light-tight cut in each fiber. The precision of the reconstructed cylindrical dose distribution was evaluated using a Poisson modeling of the acquired light signals and the accuracy of the interpolated 3D dose was evaluated using an IMRT clinical plan for a prostate case.Results: Straight scintillating fiber patterns with light-tight cuts were the most accurate in cylindrical dose reconstruction, showing less than 0.5 mm distance-to-agreement in dose gradients and a mean local dose difference of less than 0.2% in the high dose region for a 10 × 10 cm{sup 2

  16. Clinical Study of 3D Imaging and 3D Printing Technique for Patient-Specific Instrumentation in Total Knee Arthroplasty.

    PubMed

    Qiu, Bing; Liu, Fei; Tang, Bensen; Deng, Biyong; Liu, Fang; Zhu, Weimin; Zhen, Dong; Xue, Mingyuan; Zhang, Mingjiao

    2017-01-25

    Patient-specific instrumentation (PSI) was designed to improve the accuracy of preoperative planning and postoperative prosthesis positioning in total knee arthroplasty (TKA). However, better understanding needs to be achieved due to the subtle nature of the PSI systems. In this study, 3D printing technique based on the image data of computed tomography (CT) has been utilized for optimal controlling of the surgical parameters. Two groups of TKA cases have been randomly selected as PSI group and control group with no significant difference of age and sex (p > 0.05). The PSI group is treated with 3D printed cutting guides whereas the control group is treated with conventional instrumentation (CI). By evaluating the proximal osteotomy amount, distal osteotomy amount, valgus angle, external rotation angle, and tibial posterior slope angle of patients, it can be found that the preoperative quantitative assessment and intraoperative changes can be controlled with PSI whereas CI is relied on experience. In terms of postoperative parameters, such as hip-knee-ankle (HKA), frontal femoral component (FFC), frontal tibial component (FTC), and lateral tibial component (LTC) angles, there is a significant improvement in achieving the desired implant position (p < 0.05). Assigned from the morphology of patients' knees, the PSI represents the convergence of congruent designs with current personalized treatment tools. The PSI can achieve less extremity alignment and greater accuracy of prosthesis implantation compared against control method, which indicates potential for optimal HKA, FFC, and FTC angles.

  17. MESA: A 3-D Eulerian hydrocode for penetration mechanics studies

    SciTech Connect

    Mandell, D.A.; Holian, K.S.; Henninger, R.

    1991-01-01

    We describe an explicit, finite-difference hydrocode, called MESA, and compare calculations to metal and ceramic plate impacts with spall and to Taylor cylinder tests. The MESA code was developed with support from DARPA, the Army and the Marine Corps for use in armor/anti-armor problems primarily, but the code has been used for a number of other applications. MESA includes 2-D and 3-D Eulerian hydrodynamics, a number of material strength and fracture models, and a programmed burn high explosives model. 15 refs., 4 figs.

  18. Study on 3D CFBG vibration sensor and its application

    NASA Astrophysics Data System (ADS)

    Nan, Qiuming; Li, Sheng

    2016-03-01

    A novel variety of three dimensional (3D) vibration sensor based on chirped fiber Bragg grating (CFBG) is developed to measure 3D vibration in the mechanical equipment field. The sensor is composed of three independent vibration sensing units. Each unit uses double matched chirped gratings as sensing elements, and the sensing signal is processed by the edge filtering demodulation method. The structure and principle of the sensor are theoretically analyzed, and its performances are obtained from some experiments and the results are as follows: operating frequency range of the sensor is 10 Hz‒500 Hz; acceleration measurement range is 2 m·s-2‒30 m·s-2; sensitivity is about 70 mV/m·s-2; crosstalk coefficient is greater than 22 dB; self-compensation for temperature is available. Eventually the sensor is applied to monitor the vibration state of radiation pump. Seen from its experiments and applications, the sensor has good sensing performances, which can meet a certain requirement for some engineering measurement.

  19. Markerless 3D motion capture for animal locomotion studies

    PubMed Central

    Sellers, William Irvin; Hirasaki, Eishi

    2014-01-01

    ABSTRACT Obtaining quantitative data describing the movements of animals is an essential step in understanding their locomotor biology. Outside the laboratory, measuring animal locomotion often relies on video-based approaches and analysis is hampered because of difficulties in calibration and often the limited availability of possible camera positions. It is also usually restricted to two dimensions, which is often an undesirable over-simplification given the essentially three-dimensional nature of many locomotor performances. In this paper we demonstrate a fully three-dimensional approach based on 3D photogrammetric reconstruction using multiple, synchronised video cameras. This approach allows full calibration based on the separation of the individual cameras and will work fully automatically with completely unmarked and undisturbed animals. As such it has the potential to revolutionise work carried out on free-ranging animals in sanctuaries and zoological gardens where ad hoc approaches are essential and access within enclosures often severely restricted. The paper demonstrates the effectiveness of video-based 3D photogrammetry with examples from primates and birds, as well as discussing the current limitations of this technique and illustrating the accuracies that can be obtained. All the software required is open source so this can be a very cost effective approach and provides a methodology of obtaining data in situations where other approaches would be completely ineffective. PMID:24972869

  20. A Mechanistic Study of Wetting Superhydrophobic Porous 3D Meshes.

    PubMed

    Yohe, Stefan T; Freedman, Jonathan D; Falde, Eric J; Colson, Yolonda L; Grinstaff, Mark W

    2013-08-07

    Superhydrophobic, porous, 3D materials composed of poly( ε -caprolactone) (PCL) and the hydrophobic polymer dopant poly(glycerol monostearate- co- ε -caprolactone) (PGC-C18) are fabricated using the electrospinning technique. These 3D materials are distinct from 2D superhydrophobic surfaces, with maintenance of air at the surface as well as within the bulk of the material. These superhydrophobic materials float in water, and when held underwater and pressed, an air bubble is released and will rise to the surface. By changing the PGC-C18 doping concentration in the meshes and/or the fiber size from the micro- to nanoscale, the long-term stability of the entrapped air layer is controlled. The rate of water infiltration into the meshes, and the resulting displacement of the entrapped air, is quantitatively measured using X-ray computed tomography. The properties of the meshes are further probed using surfactants and solvents of different surface tensions. Finally, the application of hydraulic pressure is used to quantify the breakthrough pressure to wet the meshes. The tools for fabrication and analysis of these superhydrophobic materials as well as the ability to control the robustness of the entrapped air layer are highly desirable for a number of existing and emerging applications.

  1. Organizational Learning Goes Virtual?: A Study of Employees' Learning Achievement in Stereoscopic 3D Virtual Reality

    ERIC Educational Resources Information Center

    Lau, Kung Wong

    2015-01-01

    Purpose: This study aims to deepen understanding of the use of stereoscopic 3D technology (stereo3D) in facilitating organizational learning. The emergence of advanced virtual technologies, in particular to the stereo3D virtual reality, has fundamentally changed the ways in which organizations train their employees. However, in academic or…

  2. Comparison of 3D-OP-OSEM and 3D-FBP reconstruction algorithms for High-Resolution Research Tomograph studies: effects of randoms estimation methods

    NASA Astrophysics Data System (ADS)

    van Velden, Floris H. P.; Kloet, Reina W.; van Berckel, Bart N. M.; Wolfensberger, Saskia P. A.; Lammertsma, Adriaan A.; Boellaard, Ronald

    2008-06-01

    The High-Resolution Research Tomograph (HRRT) is a dedicated human brain positron emission tomography (PET) scanner. Recently, a 3D filtered backprojection (3D-FBP) reconstruction method has been implemented to reduce bias in short duration frames, currently observed in 3D ordinary Poisson OSEM (3D-OP-OSEM) reconstructions. Further improvements might be expected using a new method of variance reduction on randoms (VRR) based on coincidence histograms instead of using the delayed window technique (DW) to estimate randoms. The goal of this study was to evaluate VRR in combination with 3D-OP-OSEM and 3D-FBP reconstruction techniques. To this end, several phantom studies and a human brain study were performed. For most phantom studies, 3D-OP-OSEM showed higher accuracy of observed activity concentrations with VRR than with DW. However, both positive and negative deviations in reconstructed activity concentrations and large biases of grey to white matter contrast ratio (up to 88%) were still observed as a function of scan statistics. Moreover 3D-OP-OSEM+VRR also showed bias up to 64% in clinical data, i.e. in some pharmacokinetic parameters as compared with those obtained with 3D-FBP+VRR. In the case of 3D-FBP, VRR showed similar results as DW for both phantom and clinical data, except that VRR showed a better standard deviation of 6-10%. Therefore, VRR should be used to correct for randoms in HRRT PET studies.

  3. Integrated QSAR study for inhibitors of hedgehog signal pathway against multiple cell lines:a collaborative filtering method

    PubMed Central

    2012-01-01

    Background The Hedgehog Signaling Pathway is one of signaling pathways that are very important to embryonic development. The participation of inhibitors in the Hedgehog Signal Pathway can control cell growth and death, and searching novel inhibitors to the functioning of the pathway are in a great demand. As the matter of fact, effective inhibitors could provide efficient therapies for a wide range of malignancies, and targeting such pathway in cells represents a promising new paradigm for cell growth and death control. Current research mainly focuses on the syntheses of the inhibitors of cyclopamine derivatives, which bind specifically to the Smo protein, and can be used for cancer therapy. While quantitatively structure-activity relationship (QSAR) studies have been performed for these compounds among different cell lines, none of them have achieved acceptable results in the prediction of activity values of new compounds. In this study, we proposed a novel collaborative QSAR model for inhibitors of the Hedgehog Signaling Pathway by integration the information from multiple cell lines. Such a model is expected to substantially improve the QSAR ability from single cell lines, and provide useful clues in developing clinically effective inhibitors and modifications of parent lead compounds for target on the Hedgehog Signaling Pathway. Results In this study, we have presented: (1) a collaborative QSAR model, which is used to integrate information among multiple cell lines to boost the QSAR results, rather than only a single cell line QSAR modeling. Our experiments have shown that the performance of our model is significantly better than single cell line QSAR methods; and (2) an efficient feature selection strategy under such collaborative environment, which can derive the commonly important features related to the entire given cell lines, while simultaneously showing their specific contributions to a specific cell-line. Based on feature selection results, we have

  4. A quantitative structure-activity relationship (QSAR) study of some diaryl urea derivatives of B-RAF inhibitors

    PubMed Central

    Sadeghian-Rizi, Sedighe; Sakhteman, Amirhossein; Hassanzadeh, Farshid

    2016-01-01

    In the current study, both ligand-based molecular docking and receptor-based quantitative structure activity relationships (QSAR) modeling were performed on 35 diaryl urea derivative inhibitors of V600EB-RAF. In this QSAR study, a linear (multiple linear regressions) and a nonlinear (partial least squares least squares support vector machine (PLS-LS-SVM)) were used and compared. The predictive quality of the QSAR models was tested for an external set of 31 compounds, randomly chosen out of 35 compounds. The results revealed the more predictive ability of PLS-LS-SVM in analysis of compounds with urea structure. The selected descriptors indicated that size, degree of branching, aromaticity, and polarizability affected the inhibition activity of these inhibitors. Furthermore, molecular docking was carried out to study the binding mode of the compounds. Docking analysis indicated some essential H-bonding and orientations of the molecules in the active site. PMID:28003837

  5. Structure Optimization of Neuraminidase Inhibitors as Potential Anti-Influenza (H1N1Inhibitors) Agents Using QSAR and Molecular Docking Studies.

    PubMed

    Inamdar, Poonam; Bhandari, Shashikant; Sonawane, Bhagyashri; Hole, Asha; Jadhav, Chintamani

    2014-01-01

    The urgent need of neuraminidase inhibitors (NI) has provided an impetus for understanding the structure requisite at molecular level. Our search for selective inhibitors of neuraminidase has led to the identification of pharmacophoric requirements at various positions around acyl thiourea pharmacophore. The main objective of present study is to develop selective NI, with least toxicity and drug like ADMET properties. Electronic, Steric requirements were defined using kohnone nearest neighbour- molecular field analysis (kNN-MFA) model of 3D-QSAR studies. Results generated by QSAR studies showed that model has good internal as well as external predictivity. Such defined requirements were used to generate new chemical entities which exhibit higher promising predicted activities. To check selective binding of designed NCE's docking studies were carried out using the crystal structure of the neuraminidase enzyme having co-crystallized ligand Oseltamivir. Thus, molecular modelling provided a good platform to optimize the acyl thiourea pharmacophore for designing its derivatives having potent anti-viral activity.

  6. QSAR and Docking Studies on Capsazepine Derivatives for Immunomodulatory and Anti-Inflammatory Activity

    PubMed Central

    Shukla, Aparna; Sharma, Pooja; Prakash, Om; Singh, Monika; Kalani, Komal; Khan, Feroz; Bawankule, Dnyaneshwar Umrao; Luqman, Suaib; Srivastava, Santosh Kumar

    2014-01-01

    Capsazepine, an antagonist of capsaicin, is discovered by the structure and activity relationship. In previous studies it has been found that capsazepine has potency for immunomodulation and anti-inflammatory activity and emerging as a favourable target in quest for efficacious and safe anti-inflammatory drug. Thus, a 2D quantitative structural activity relationship (QSAR) model against target tumor necrosis factor-α (TNF-α) was developed using multiple linear regression method (MLR) with good internal prediction (r2 = 0.8779) and external prediction (r2pred = 0.5865) using Discovery Studio v3.5 (Accelrys, USA). The predicted activity was further validated by in vitro experiment. Capsazepine was tested in lipopolysaccharide (LPS) induced inflammation in peritoneal mouse macrophages. Anti-inflammatory profile of capsazepine was assessed by its potency to inhibit the production of inflammatory mediator TNF-α. The in vitro experiment indicated that capsazepine is an efficient anti-inflammatory agent. Since, the developed QSAR model showed significant correlations between chemical structure and anti-inflammatory activity, it was successfully applied in the screening of forty-four virtual derivatives of capsazepine, which finally afforded six potent derivatives, CPZ-29, CPZ-30, CPZ-33, CPZ-34, CPZ-35 and CPZ-36. To gain more insights into the molecular mechanism of action of capsazepine and its derivatives, molecular docking and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were performed. The results of QSAR, molecular docking, in silico ADMET screening and in vitro experimental studies provide guideline and mechanistic scope for the identification of more potent anti-inflammatory & immunomodulatory drug. PMID:25003344

  7. A comparative study between a rectilinear 3-D seismic survey and a concentric-circle 3-D seismic survey

    SciTech Connect

    Maldonado, B.; Hussein, H.S.

    1994-12-31

    Due to the rectilinear nature of the previous 3D seismic survey, the details necessary for proper interpretation were absent. Theoretically, concentric 3D seismic technology may provide an avenue for gaining more and higher quality data coverage. Problems associated with recording a rectilinear 3D seismic grid over the salt dome in this area have created the need to investigate the use of such procedures as the concentric-circle 3D seismic acquisition technique. The difficulty of imaging salt dome flanks with conventional rectilinear 3D seismic may be a result of the inability to precisely predict the lateral velocity-field variation adjacent to both salt and sediments. The dramatic difference in the interval velocities of salt and sediments causes the returning ray to severely deviate from being a hyperbolic path. This hampers the ability to predict imaging points near the salt/sediment interface. Perhaps the most difficult areas to image with rectilinear seismic surveys are underneath salt overhangs. Modeling suggests that a significant increase in the number of rays captured from beneath a salt overhang can be achieved with the concentric-circle method. This paper demonstrates the use of the ``circle shoot`` on a survey conducted over a salt dome in the Gulf of Mexico. A total of 80 concentric circles cover an area which is equivalent to 31,000 acres. The final post-stack data were sorted into bins with dimensions of 25 meters by 25 meters. A comparison of 3D rectilinear shooting vs. 3D concentric circle shooting over the same area will show an improvement in data quality and signal-to-noise characteristics.

  8. Biomacromolecular quantitative structure-activity relationship (BioQSAR): a proof-of-concept study on the modeling, prediction and interpretation of protein-protein binding affinity

    NASA Astrophysics Data System (ADS)

    Zhou, Peng; Wang, Congcong; Tian, Feifei; Ren, Yanrong; Yang, Chao; Huang, Jian

    2013-01-01

    Quantitative structure-activity relationship (QSAR), a regression modeling methodology that establishes statistical correlation between structure feature and apparent behavior for a series of congeneric molecules quantitatively, has been widely used to evaluate the activity, toxicity and property of various small-molecule compounds such as drugs, toxicants and surfactants. However, it is surprising to see that such useful technique has only very limited applications to biomacromolecules, albeit the solved 3D atom-resolution structures of proteins, nucleic acids and their complexes have accumulated rapidly in past decades. Here, we present a proof-of-concept paradigm for the modeling, prediction and interpretation of the binding affinity of 144 sequence-nonredundant, structure-available and affinity-known protein complexes (Kastritis et al. Protein Sci 20:482-491, 2011) using a biomacromolecular QSAR (BioQSAR) scheme. We demonstrate that the modeling performance and predictive power of BioQSAR are comparable to or even better than that of traditional knowledge-based strategies, mechanism-type methods and empirical scoring algorithms, while BioQSAR possesses certain additional features compared to the traditional methods, such as adaptability, interpretability, deep-validation and high-efficiency. The BioQSAR scheme could be readily modified to infer the biological behavior and functions of other biomacromolecules, if their X-ray crystal structures, NMR conformation assemblies or computationally modeled structures are available.

  9. 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.

  10. Structure-hepatoprotective activity relationship study of sesquiterpene lactones: A QSAR analysis

    NASA Astrophysics Data System (ADS)

    Paukku, Yuliya; Rasulev, Bakhtiyor; Syrov, Vladimir; Khushbaktova, Zainab; Leszczynski, Jerzy

    This study has been carried out using quantitative structure-activity relationship analysis (QSAR) for 22 sesquiterpene lactones to correlate and predict their hepatoprotective activity. Sesquiterpenoids, the largest class of terpenoids, are a widespread group of substances occurring in various plant organisms. QSAR analysis was carried out using methods such as genetic algorithm for variables selection among generated and calculated descriptors and multiple linear regression analysis. Quantum-chemical calculations have been performed by density functional theory at B3LYP/6-311G(d, p) level for evaluation of electronic properties using reference geometries optimized by semi-empirical AM1 approach. Three models describing hepatoprotective activity values for series of sesquiterpene lactones are proposed. The obtained models are useful for description of sesquiterpene lactones hepatoprotective activity and can be used to estimate the hepatoprotective activity of new substituted sesquiterpene lactones. The models obtained in our study show not only statistical significance, but also good predictive ability. The estimated predictive ability (rtest2) of these models lies within 0.942-0.969.

  11. In silico study combining docking and QSAR methods on a series of matrix metalloproteinase 13 inhibitors.

    PubMed

    Xi, Lili; Li, Shuyan; Yao, Xiaojun; Wei, Yuhui; Li, Jiazhong; Liu, Huanxiang; Wu, Xin'an

    2014-11-01

    Matrix metalloproteinase 13 (MMP-13) plays an important role in the degradation of articular cartilage and has been considered as an attractive target for the treatment of osteoarthritis; hence, the development of efficient inhibitors of MMP-13 has become a hot study field. Taking a series of carboxylic acid-based MMP-13 inhibitors as research object, this work utilized an extended QSAR method to analyze the structure-activity relationships. We focused on two important topics in QSAR: bioactive conformation and descriptors. Firstly, molecular docking was carried out to dock all molecules into the MMP-13 active site in order to obtain the bioactive conformation. Secondly, based on the docked complex, descriptors characterizing receptor-ligand interactions and the ligand structure were calculated. Thirdly, a genetic algorithm (GA) and multiple linear regression (MLR) were employed to select important descriptors related to inhibitory activities, simultaneously, to build the predictive model. The built model gave satisfactory results with highly accurate fitting and strong external predictive abilities for chemicals not used in model development. Furthermore, the selected descriptors were explored to elucidate important factors influencing the inhibition activities. This study demonstrates that the selection strategy of the docking-guided bioactive conformation is rational and useful in predicting MMP-13 inhibitor activities, and receptor-ligand complex descriptors have an advantage over directly reflecting receptor-ligand interactions.

  12. Computational study of 3-D Benard convection with gravitational modulation

    NASA Technical Reports Server (NTRS)

    Biringen, S.; Peltier, L. J.

    1989-01-01

    In this numerical study the effects of a modulated gravitational field on three-dimensional Rayleigh-Benard convection with heating from above or from below is investigated. The full, nonlinear, time-dependent, Boussinesq Navier-Stokes equations and the energy equation are solved by a semiimplicit, pseudo-spectral procedure. This study has been motivated by the need to better understand the effects of vibration (G-Jitter) on fluids systems especially in the low gravity environment.

  13. Towards a collaborative and interoperable 3D Building database - A case study in Walloon region

    NASA Astrophysics Data System (ADS)

    Hajji, R.; Billen, R.

    2012-10-01

    The definition of a 3D Reference model is the prerequisite for increasing data interoperability and facing regional, national and international challenges around geographic information. Such action requires investigation of 3D user requirements and a collaborative framework to reach a consensus on common 3D data specifications. The paper presents premise reflexions about relevant issues to shape efforts towards a methodological and generic approach for dealing with a collaborative 3D reference model as a fundamental building block of 3D GIS collaborative solution. As a pilot project, we demonstrate, through a case study of the Liege city in Belgium, how data collected from different providers in Walloon region can be reengineered and then integrated in a 3D collaborative interoperable database compatible with CityGML.

  14. A 3D optical study of Low Surface Brightness galaxies

    NASA Astrophysics Data System (ADS)

    Chemin, L.; Amram, P.; Carignan, C.; Balkowski, C.; van Driel, W.; Cayatte, V.; Hernandez, O.

    2004-12-01

    Integral field spectroscopy observations of the ionized gas in Low Surface Brightness Galaxies (LSBs) are presented. The goal of this study is to map their kinematics at high angular resolution and to study their dark matter (DM) distribution. For that purpose, we have used Fabry-Perot observations obtained at the CFH and ESO 3.6m telescopes. The new contribution of highly resolved velocity fields is crucial to study the role of non-circular motions on the dynamics of LSBs, and particularly on the shape of their DM halo profile (cusp- or core- dominated halo). Here are shown some examples of galaxies in which such motions exist in their central parts and prevent from determining the accurate shape of their DM halo.

  15. Combined QSAR and molecule docking studies on predicting P-glycoprotein inhibitors

    NASA Astrophysics Data System (ADS)

    Tan, Wen; Mei, Hu; Chao, Li; Liu, Tengfei; Pan, Xianchao; Shu, Mao; Yang, Li

    2013-12-01

    P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter. The over expression of P-gp leads to the development of multidrug resistance (MDR), which is a major obstacle to effective treatment of cancer. Thus, designing effective P-gp inhibitors has an extremely important role in the overcoming MDR. In this paper, both ligand-based quantitative structure-activity relationship (QSAR) and receptor-based molecular docking are used to predict P-gp inhibitors. The results show that each method achieves good prediction performance. According to the results of tenfold cross-validation, an optimal linear SVM model with only three descriptors is established on 857 training samples, of which the overall accuracy (Acc), sensitivity, specificity, and Matthews correlation coefficient are 0.840, 0.873, 0.813, and 0.683, respectively. The SVM model is further validated by 418 test samples with the overall Acc of 0.868. Based on a homology model of human P-gp established, Surflex-dock is also performed to give binding free energy-based evaluations with the overall accuracies of 0.823 for the test set. Furthermore, a consensus evaluation is also performed by using these two methods. Both QSAR and molecular docking studies indicate that molecular volume, hydrophobicity and aromaticity are three dominant factors influencing the inhibitory activities.

  16. Combined QSAR and molecule docking studies on predicting P-glycoprotein inhibitors.

    PubMed

    Tan, Wen; Mei, Hu; Chao, Li; Liu, Tengfei; Pan, Xianchao; Shu, Mao; Yang, Li

    2013-12-01

    P-glycoprotein (P-gp) is an ATP-binding cassette multidrug transporter. The over expression of P-gp leads to the development of multidrug resistance (MDR), which is a major obstacle to effective treatment of cancer. Thus, designing effective P-gp inhibitors has an extremely important role in the overcoming MDR. In this paper, both ligand-based quantitative structure-activity relationship (QSAR) and receptor-based molecular docking are used to predict P-gp inhibitors. The results show that each method achieves good prediction performance. According to the results of tenfold cross-validation, an optimal linear SVM model with only three descriptors is established on 857 training samples, of which the overall accuracy (Acc), sensitivity, specificity, and Matthews correlation coefficient are 0.840, 0.873, 0.813, and 0.683, respectively. The SVM model is further validated by 418 test samples with the overall Acc of 0.868. Based on a homology model of human P-gp established, Surflex-dock is also performed to give binding free energy-based evaluations with the overall accuracies of 0.823 for the test set. Furthermore, a consensus evaluation is also performed by using these two methods. Both QSAR and molecular docking studies indicate that molecular volume, hydrophobicity and aromaticity are three dominant factors influencing the inhibitory activities.

  17. QSAR Study for Carcinogenic Potency of Aromatic Amines Based on GEP and MLPs

    PubMed Central

    Song, Fucheng; Zhang, Anling; Liang, Hui; Cui, Lianhua; Li, Wenlian; Si, Hongzong; Duan, Yunbo; Zhai, Honglin

    2016-01-01

    A new analysis strategy was used to classify the carcinogenicity of aromatic amines. The physical-chemical parameters are closely related to the carcinogenicity of compounds. Quantitative structure activity relationship (QSAR) is a method of predicting the carcinogenicity of aromatic amine, which can reveal the relationship between carcinogenicity and physical-chemical parameters. This study accessed gene expression programming by APS software, the multilayer perceptrons by Weka software to predict the carcinogenicity of aromatic amines, respectively. All these methods relied on molecular descriptors calculated by CODESSA software and eight molecular descriptors were selected to build function equations. As a remarkable result, the accuracy of gene expression programming in training and test sets are 0.92 and 0.82, the accuracy of multilayer perceptrons in training and test sets are 0.84 and 0.74 respectively. The precision of the gene expression programming is obviously superior to multilayer perceptrons both in training set and test set. The QSAR application in the identification of carcinogenic compounds is a high efficiency method. PMID:27854309

  18. Quantification of contributions of molecular fragments for eye irritation of organic chemicals using QSAR study.

    PubMed

    Kar, Supratik; Roy, Kunal

    2014-05-01

    The eye irritation potential of chemicals has largely been evaluated using the Draize rabbit-eye test for a very long time. The Draize eye-irritation data on 38 compounds established by the European Center for Ecotoxicology and Toxicology of Chemicals (ECETOC) has been used in the present quantitative structure-activity relationship (QSAR) analysis in order to predict molar-adjusted eye scores (MES) and determine possible structural requisites and attributes that are primarily responsible for the eye irritation caused by the studied solutes. The developed model was rigorously validated internally as well as externally by applying principles of the Organization for Economic Cooperation and Development (OECD). The test for applicability domain was also carried out in order to check the reliability of the predictions. Important fragments contributing to higher MES values of the solutes were identified through critical analysis and interpretation of the developed model. Considering all the identified structural attributes, one can choose or design safe solutes with low eye irritant properties. The presented approach suggests a model for use in the context of virtual screening of relevant solute libraries. The developed QSAR model can be used to predict existing as well as future chemicals falling within the applicability domain of the model in order to reduce the use of animals.

  19. DIY 3D printing of custom orthopaedic implants: a proof of concept study.

    PubMed

    Frame, Mark; Leach, William

    2014-03-01

    3D printing is an emerging technology that is primarily used for aiding the design and prototyping of implants. As this technology has evolved it has now become possible to produce functional and definitive implants manufactured using a 3D printing process. This process, however, previously required a large financial investment in complex machinery and professionals skilled in 3D product design. Our pilot study's aim was to design and create a 3D printed custom orthopaedic implant using only freely available consumer hardware and software.

  20. 3D MHD Study of Helias and Heliotron

    DTIC Science & Technology

    1992-09-01

    Loss and Radial Electric Field in Wendelstein VII-A Stellarator ; Oct. 1991 N IFS-i 18 Y. Kondoh and Y. Hosaka, Kernel Optimum Nearly-analytical...30 September -- 7 October 1992 IAEA-CN-56/D-1 -4 31) MIlD Study or Ielias and lIfliotron 1’. Hayashi. T. Sato, W. Lotz. P. Merkel, J. Nuifirenbyerg...AGENCY Ŕ •JI" " FOURTEENTH INTERNATIONAL CONFERENCE ON PLASMA Zo PHYSICS AND CONTROLLED NUCLEAR FUSION RESEARCH Wirzburg, Germany, 30 September - 7

  1. Scalable nanohelices for predictive studies and enhanced 3D visualization.

    PubMed

    Meagher, Kwyn A; Doblack, Benjamin N; Ramirez, Mercedes; Davila, Lilian P

    2014-11-12

    Spring-like materials are ubiquitous in nature and of interest in nanotechnology for energy harvesting, hydrogen storage, and biological sensing applications. For predictive simulations, it has become increasingly important to be able to model the structure of nanohelices accurately. To study the effect of local structure on the properties of these complex geometries one must develop realistic models. To date, software packages are rather limited in creating atomistic helical models. This work focuses on producing atomistic models of silica glass (SiO₂) nanoribbons and nanosprings for molecular dynamics (MD) simulations. Using an MD model of "bulk" silica glass, two computational procedures to precisely create the shape of nanoribbons and nanosprings are presented. The first method employs the AWK programming language and open-source software to effectively carve various shapes of silica nanoribbons from the initial bulk model, using desired dimensions and parametric equations to define a helix. With this method, accurate atomistic silica nanoribbons can be generated for a range of pitch values and dimensions. The second method involves a more robust code which allows flexibility in modeling nanohelical structures. This approach utilizes a C++ code particularly written to implement pre-screening methods as well as the mathematical equations for a helix, resulting in greater precision and efficiency when creating nanospring models. Using these codes, well-defined and scalable nanoribbons and nanosprings suited for atomistic simulations can be effectively created. An added value in both open-source codes is that they can be adapted to reproduce different helical structures, independent of material. In addition, a MATLAB graphical user interface (GUI) is used to enhance learning through visualization and interaction for a general user with the atomistic helical structures. One application of these methods is the recent study of nanohelices via MD simulations for

  2. Scalable Nanohelices for Predictive Studies and Enhanced 3D Visualization

    PubMed Central

    Meagher, Kwyn A.; Doblack, Benjamin N.; Ramirez, Mercedes; Davila, Lilian P.

    2014-01-01

    Spring-like materials are ubiquitous in nature and of interest in nanotechnology for energy harvesting, hydrogen storage, and biological sensing applications.  For predictive simulations, it has become increasingly important to be able to model the structure of nanohelices accurately.  To study the effect of local structure on the properties of these complex geometries one must develop realistic models.  To date, software packages are rather limited in creating atomistic helical models.  This work focuses on producing atomistic models of silica glass (SiO2) nanoribbons and nanosprings for molecular dynamics (MD) simulations. Using an MD model of “bulk” silica glass, two computational procedures to precisely create the shape of nanoribbons and nanosprings are presented.  The first method employs the AWK programming language and open-source software to effectively carve various shapes of silica nanoribbons from the initial bulk model, using desired dimensions and parametric equations to define a helix.  With this method, accurate atomistic silica nanoribbons can be generated for a range of pitch values and dimensions.  The second method involves a more robust code which allows flexibility in modeling nanohelical structures.  This approach utilizes a C++ code particularly written to implement pre-screening methods as well as the mathematical equations for a helix, resulting in greater precision and efficiency when creating nanospring models.  Using these codes, well-defined and scalable nanoribbons and nanosprings suited for atomistic simulations can be effectively created.  An added value in both open-source codes is that they can be adapted to reproduce different helical structures, independent of material.  In addition, a MATLAB graphical user interface (GUI) is used to enhance learning through visualization and interaction for a general user with the atomistic helical structures.  One application of these methods is the recent study of nanohelices

  3. High pressure system for 3-D study of elastic anisotropy

    NASA Astrophysics Data System (ADS)

    Lokajicek, T.; Pros, Z.; Klima, K.

    2003-04-01

    New high pressure system was designed for the study of elastic anisotropy of condensed matter under high confining pressure up to 700 MPa. Simultaneously could be measured dynamic and static parameters: a) dynamic parameters by ultrasonic sounding, b) static parameters by measuring of spherical sample deformation. The measurement is carried out on spherical samples diameter 50 +/- 0.01 mm. Higher value of confining pressure was reached due to the new construction of sample positioning unit. The positioning unit is equipped with two Portecap step motors, which are located inside the vessel and make possible to rotate with the sphere and couple of piezoceramic transducers. Sample deformation is measured in the same direction as ultrasonic signal travel time. Only electric leads connects inner part of high pressure vessel with surrounding environment. Experimental set up enables: - simultaneous P-wave ultrasonic sounding, - measurement of current sample deformation at sounding points, - measurement of current value of confining pressure and - measurement of current stress media temperature. Air driven high pressure pump Haskel is used to produce high value of confining pressure up to 700 MPa. Ultrasonic signals are recorded by digital scope Agilent 54562 with sampling frequency 100 MHz. Control and measuring software was developed under Agilent VEE software environment working under MS Win 2000 operating system. Measuring set up was tested by measurement of monomineral spherical samples of quartz and corundum. Both of them have trigonal symmetry. The measurement showed that the P-wave velocity range of quartz was between 5.7-7.0 km/sec. and velocity range of corundum was between 9.7-10.9 km/sec. High pressure resistant LVDT transducers Mesing together with Intronix electronic unit were used to monitor sample deformation. Sample deformation is monitored with the accuracy of 0.1 micron. All test measurements proved the good accuracy of the whole measuring set up. This

  4. Developing and Testing a 3d Cadastral Data Model a Case Study in Australia

    NASA Astrophysics Data System (ADS)

    Aien, A.; Kalantari, M.; Rajabifard, A.; Williamson, I. P.; Shojaei, D.

    2012-07-01

    and physical extent of 3D properties and associated interests. The data model extends the traditional cadastral requirements to cover other applications such as urban planning and land valuation and taxation. A demonstration of a test system on the proposed data model is also presented. The test is based on a case study in Victoria, Australia to evaluate the effectiveness of the data model.

  5. Experimental Studies on the 3D Macro- and Microphysics of Magnetic Reconnection

    NASA Astrophysics Data System (ADS)

    Jara-Almonte, J.; Ji, H.; Yamada, M.; Yoo, J.; Fox, W. R., II

    2015-12-01

    Magnetic reconnection has been extensively studied in 2D geometries for many decades and considerable progress has been made in understating 2D reconnection physics, yet in real plasmas reconnection is fundamentally 3D in nature. Only recently has it become possible to study 3D reconnection using simulations, however some initial results have suggested that the inclusion of 3D effects does not strongly affect the basic properties of reconnection (e.g. reconnection rate or particle acceleration). Yet on the other hand, previous experiments, without direct 3D measurements, have implied that 3D effects could be important even in a quasi-2D system. Here we experimentally study both the (1) macro- and (2) microphysics of 3D reconnection in order to directly test the importance of 3D effects in a quasi-2D experiment. Using fully simultaneous 3D measurements, it is shown that during highly driven reconnection the macroscopic structure of the current sheet can become strongly 3D despite an essentially 2D upstream region. The correlation length along the current sheet is measured to be far shorter than suggested by kinetic simulations. Results from new experiments with stronger reconnection drive and diagnostics designed to estimate the 3D reconnection rate will be discussed. With regards to (2), the 3D microphysics, new diagnostics capable of measuring fluctuations at frequencies up to the electron cyclotron frequency (~ 300 MHz) have been developed and have identified the presence of very high frequency waves (~ 100 MHz) during asymmetric reconnection, localized to the low-density side. The detailed properties of these waves, including the measured power spectra and dispersion relation, will be discussed and compared with both previous satellite observations of high-frequency waves as well as with theoretical predictions on the generation of whistler waves during reconnection.

  6. Understanding Human Perception of Building Categories in Virtual 3d Cities - a User Study

    NASA Astrophysics Data System (ADS)

    Tutzauer, P.; Becker, S.; Niese, T.; Deussen, O.; Fritsch, D.

    2016-06-01

    Virtual 3D cities are becoming increasingly important as a means of visually communicating diverse urban-related information. To get a deeper understanding of a human's cognitive experience of virtual 3D cities, this paper presents a user study on the human ability to perceive building categories (e.g. residential home, office building, building with shops etc.) from geometric 3D building representations. The study reveals various dependencies between geometric properties of the 3D representations and the perceptibility of the building categories. Knowledge about which geometries are relevant, helpful or obstructive for perceiving a specific building category is derived. The importance and usability of such knowledge is demonstrated based on a perception-guided 3D building abstraction process.

  7. Possibility of reconstruction of dental plaster cast from 3D digital study models

    PubMed Central

    2013-01-01

    Objectives To compare traditional plaster casts, digital models and 3D printed copies of dental plaster casts based on various criteria. To determine whether 3D printed copies obtained using open source system RepRap can replace traditional plaster casts in dental practice. To compare and contrast the qualities of two possible 3D printing options – open source system RepRap and commercially available 3D printing. Design and settings A method comparison study on 10 dental plaster casts from the Orthodontic department, Department of Stomatology, 2nd medical Faulty, Charles University Prague, Czech Republic. Material and methods Each of 10 plaster casts were scanned by inEos Blue scanner and the printed on 3D printer RepRap [10 models] and ProJet HD3000 3D printer [1 model]. Linear measurements between selected points on the dental arches of upper and lower jaws on plaster casts and its 3D copy were recorded and statistically analyzed. Results 3D printed copies have many advantages over traditional plaster casts. The precision and accuracy of the RepRap 3D printed copies of plaster casts were confirmed based on the statistical analysis. Although the commercially available 3D printing enables to print more details than the RepRap system, it is expensive and for the purpose of clinical use can be replaced by the cheaper prints obtained from RepRap printed copies. Conclusions Scanning of the traditional plaster casts to obtain a digital model offers a pragmatic approach. The scans can subsequently be used as a template to print the plaster casts as required. Using 3D printers can replace traditional plaster casts primarily due to their accuracy and price. PMID:23721330

  8. A DFT-based toxicity QSAR study of aromatic hydrocarbons to Vibrio fischeri: Consideration of aqueous freely dissolved concentration.

    PubMed

    Wang, Ying; Yang, Xianhai; Wang, Juying; Cong, Yi; Mu, Jingli; Jin, Fei

    2016-05-05

    In the present study, quantitative structure-activity relationship (QSAR) techniques based on toxicity mechanism and density functional theory (DFT) descriptors were adopted to develop predictive models for the toxicity of alkylated and parent aromatic hydrocarbons to Vibrio fischeri. The acute toxicity data of 17 aromatic hydrocarbons from both literature and our experimental results were used to construct QSAR models by partial least squares (PLS) analysis. With consideration of the toxicity process, the partition of aromatic hydrocarbons between water phase and lipid phase and their interaction with the target biomolecule, the optimal QSAR model was obtained by introducing aqueous freely dissolved concentration. The high statistical values of R(2) (0.956) and Q(CUM)(2) (0.942) indicated that the model has good goodness-of-fit, robustness and internal predictive power. The average molecular polarizability (α) and several selected thermodynamic parameters reflecting the intermolecular interactions played important roles in the partition of aromatic hydrocarbons between the water phase and biomembrane. Energy of the highest occupied molecular orbital (E(HOMO)) was the most influential descriptor which dominated the toxicity of aromatic hydrocarbons through the electron-transfer reaction with biomolecules. The results demonstrated that the adoption of freely dissolved concentration instead of nominal concentration was a beneficial attempt for toxicity QSAR modeling of hydrophobic organic chemicals.

  9. Benefits of statistical molecular design, covariance analysis, and reference models in QSAR: a case study on acetylcholinesterase

    NASA Astrophysics Data System (ADS)

    Andersson, C. David; Hillgren, J. Mikael; Lindgren, Cecilia; Qian, Weixing; Akfur, Christine; Berg, Lotta; Ekström, Fredrik; Linusson, Anna

    2015-03-01

    Scientific disciplines such as medicinal- and environmental chemistry, pharmacology, and toxicology deal with the questions related to the effects small organic compounds exhort on biological targets and the compounds' physicochemical properties responsible for these effects. A common strategy in this endeavor is to establish structure-activity relationships (SARs). The aim of this work was to illustrate benefits of performing a statistical molecular design (SMD) and proper statistical analysis of the molecules' properties before SAR and quantitative structure-activity relationship (QSAR) analysis. Our SMD followed by synthesis yielded a set of inhibitors of the enzyme acetylcholinesterase (AChE) that had very few inherent dependencies between the substructures in the molecules. If such dependencies exist, they cause severe errors in SAR interpretation and predictions by QSAR-models, and leave a set of molecules less suitable for future decision-making. In our study, SAR- and QSAR models could show which molecular sub-structures and physicochemical features that were advantageous for the AChE inhibition. Finally, the QSAR model was used for the prediction of the inhibition of AChE by an external prediction set of molecules. The accuracy of these predictions was asserted by statistical significance tests and by comparisons to simple but relevant reference models.

  10. QSAR study on the antinociceptive activity of some morphinans.

    PubMed

    Ramírez-Galicia, Guillermo; Garduño-Juárez, Ramón; Hemmateenejad, Bahram; Deeb, Omar; Deciga-Campos, Myrna; Moctezuma-Eugenio, Juan Carlos

    2007-07-01

    Quantitative structure-activity relationship studies were performed to describe and predict the antinociceptive activity of 31 morphinan derivatives reported by the US Drug Evaluation Committee in 2005 and 2006. From these, three data sets were constructed and several models were calculated following the multiple linear regression and Leave-One-Out Cross-Validation (LOO-CV) tests. In general, these models achieved good descriptive power (approximately 92%) as well as predictive power (approximately 76%), but were unable to predict an external validation set of morphinan derivatives. When artificial neural networks were applied to these models, an improvement of the predictive and external validation values was obtained. It was observed that the results of the NN models are significantly better that those obtained by multiple linear regression. In spite that the problem under investigation can be handled adequately by a linear model, a neural network does bring slight improvements in the predictive power.

  11. Improving Assistive Technology Service by Using 3D Printing: Three Case Studies.

    PubMed

    Watanabe, Takashi; Hatakeyama, Takuro; Tomiita, Mitsuru

    2015-01-01

    Assistive technology services are essential for adapting assistive devices to the individual needs of users with disabilities. In this study, we attempted to apply three-dimensional (3D) printing technology to three actual cases, and to study its use, effectiveness, and future applications. We assessed the usefulness of 3D printing technology by categorizing its utilization after reviewing the outcomes of these case studies. In future work, we aim to gather additional case studies and derive information on using 3D printing technology that will enable its effective application in the process of assistive technology services.

  12. Genre Matters: A Comparative Study on the Entertainment Effects of 3D in Cinematic Contexts

    NASA Astrophysics Data System (ADS)

    Ji, Qihao; Lee, Young Sun

    2014-09-01

    Built upon prior comparative studies of 3D and 2D films, the current project investigates the effects of 2D and 3D on viewers' perception of enjoyment, narrative engagement, presence, involvement, and flow across three movie genres (Action/fantasy vs. Drama vs. Documentary). Through a 2 by 3 mixed factorial design, participants (n = 102) were separated into two viewing conditions (2D and 3D) and watched three 15-min film segments. Result suggested both visual production methods are equally efficient in terms of eliciting people's enjoyment, narrative engagement, involvement, flow and presence, no effects of visual production method was found. In addition, through examining the genre effects in both 3D and 2D conditions, we found that 3D works better for action movies than documentaries in terms of eliciting viewers' perception of enjoyment and presence, similarly, it improves views' narrative engagement for documentaries than dramas substantially. Implications and limitations are discussed in detail.

  13. A DFT-based QSAR study on inhibition of human dihydrofolate reductase.

    PubMed

    Karabulut, Sedat; Sizochenko, Natalia; Orhan, Adnan; Leszczynski, Jerzy

    2016-11-01

    Diaminopyrimidine derivatives are frequently used as inhibitors of human dihydrofolate reductase, for example in treatment of patients whose immune system are affected by human immunodeficiency virus. Forty-seven dicyclic and tricyclic potential inhibitors of human dihydrofolate reductase were analyzed using the quantitative structure-activity analysis supported by DFT-based and DRAGON-based descriptors. The developed model yielded an RMSE deviation of 1.1 a correlation coefficient of 0.81. The prediction set was characterized by R(2)=0.60 and RMSE=3.59. Factors responsible for inhibition process were identified and discussed. The resulting model was validated via cross validation and Y-scrambling procedure. From the best model, we found several mass-related descriptors and Sanderson electronegativity-related descriptors that have the best correlations with the investigated inhibitory concentration. These descriptors reflect results from QSAR studies based on characteristics of human dihydrofolate reductase inhibitors.

  14. QSAR and docking studies of anthraquinone derivatives by similarity cluster prediction.

    PubMed

    Harsa, Alexandra M; Harsa, Teodora E; Diudea, Mircea V

    2016-01-01

    Forty anthraquinone derivatives have been downloaded from PubChem database and investigated in a quantitative structure-activity relationships (QSAR) study. The models describing log P and LD50 of this set were built up on the hypermolecule scheme that mimics the investigated receptor space; the models were validated by the leave-one-out procedure, in the external test set and in a new version of prediction by using similarity clusters. Molecular docking approach using Lamarckian Genetic Algorithm was made on this class of anthraquinones with respect to 3Q3B receptor. The best scored molecules in the docking assay were used as leaders in the similarity clustering procedure. It is demonstrated that the LD50 data of this set of anthraquinones are related to the binding energies of anthraquinone ligands to the 3Q3B receptor.

  15. QSAR Study and Molecular Design of Open-Chain Enaminones as Anticonvulsant Agents

    PubMed Central

    Garro Martinez, Juan C.; Duchowicz, Pablo R.; Estrada, Mario R.; Zamarbide, Graciela N.; Castro, Eduardo A.

    2011-01-01

    Present work employs the QSAR formalism to predict the ED50 anticonvulsant activity of ringed-enaminones, in order to apply these relationships for the prediction of unknown open-chain compounds containing the same types of functional groups in their molecular structure. Two different modeling approaches are applied with the purpose of comparing the consistency of our results: (a) the search of molecular descriptors via multivariable linear regressions; and (b) the calculation of flexible descriptors with the CORAL (CORrelation And Logic) program. Among the results found, we propose some potent candidate open-chain enaminones having ED50 values lower than 10 mg·kg−1 for corresponding pharmacological studies. These compounds are classified as Class 1 and Class 2 according to the Anticonvulsant Selection Project. PMID:22272137

  16. Boosting support vector regression in QSAR studies of bioactivities of chemical compounds.

    PubMed

    Zhou, Yan-Ping; Jiang, Jian-Hui; Lin, Wei-Qi; Zou, Hong-Yan; Wu, Hai-Long; Shen, Guo-Li; Yu, Ru-Qin

    2006-07-01

    In this paper, boosting has been coupled with SVR to develop a new method, boosting support vector regression (BSVR). BSVR is implemented by firstly constructing a series of SVR models on the various weighted versions of the original training set and then combining the predictions from the constructed SVR models to obtain integrative results by weighted median. The proposed BSVR algorithm has been used to predict toxicities of nitrobenzenes and inhibitory potency of 1-phenyl[2H]-tetrahydro-triazine-3-one analogues as inhibitors of 5-lipoxygenase. As comparisons to this method, the multiple linear regression (MLR) and conventional support vector regression (SVR) have also been investigated. Experimental results have shown that the introduction of boosting drastically enhances the generalization performance of individual SVR model and BSVR is a well-performing technique in QSAR studies superior to multiple linear regression.

  17. Are Mechanistic and Statistical QSAR Approaches Really Different? MLR Studies on 158 Cycloalkyl-Pyranones.

    PubMed

    Bhhatarai, Barun; Garg, Rajni; Gramatica, Paola

    2010-07-12

    Two parallel approaches for quantitative structure-activity relationships (QSAR) are predominant in literature, one guided by mechanistic methods (including read-across) and another by the use of statistical methods. To bridge the gap between these two approaches and to verify their main differences, a comparative study of mechanistically relevant and statistically relevant QSAR models, developed on a case study of 158 cycloalkyl-pyranones, biologically active on inhibition (Ki ) of HIV protease, was performed. Firstly, Multiple Linear Regression (MLR) based models were developed starting from a limited amount of molecular descriptors which were widely proven to have mechanistic interpretation. Then robust and predictive MLR models were developed on the same set using two different statistical approaches unbiased of input descriptors. Development of models based on Statistical I method was guided by stepwise addition of descriptors while Genetic Algorithm based selection of descriptors was used for the Statistical II. Internal validation, the standard error of the estimate, and Fisher's significance test were performed for both the statistical models. In addition, external validation was performed for Statistical II model, and Applicability Domain was verified as normally practiced in this approach. The relationships between the activity and the important descriptors selected in all the models were analyzed and compared. It is concluded that, despite the different type and number of input descriptors, and the applied descriptor selection tools or the algorithms used for developing the final model, the mechanistical and statistical approach are comparable to each other in terms of quality and also for mechanistic interpretability of modelling descriptors. Agreement can be observed between these two approaches and the better result could be a consensus prediction from both the models.

  18. 3D-Flow processor for a programmable Level-1 trigger (feasibility study)

    SciTech Connect

    Crosetto, D.

    1992-10-01

    A feasibility study has been made to use the 3D-Flow processor in a pipelined programmable parallel processing architecture to identify particles such as electrons, jets, muons, etc., in high-energy physics experiments.

  19. Per- and polyfluoro toxicity (LC(50) inhalation) study in rat and mouse using QSAR modeling.

    PubMed

    Bhhatarai, Barun; Gramatica, Paola

    2010-03-15

    Fully or partially fluorinated compounds, known as per- and polyfluorinated chemicals are widely distributed in the environment and released because of their use in different household and industrial products. Few of these long chain per- and polyfluorinated chemicals are classified as emerging pollutants, and their environmental and toxicological effects are unveiled in the literature. This has diverted the production of long chain compounds, considered as more toxic, to short chains, but concerns regarding the toxicity of both types of per- and polyfluorinated chemicals are alarming. There are few experimental data available on the environmental behavior and toxicity of these compounds, and moreover, toxicity profiles are found to be different for the types of animals and species used. Quantitative structure-activity relationship (QSAR) is applied to a combination of short and long chain per- and polyfluorinated chemicals, for the first time, to model and predict the toxicity on two species of rodents, rat (Rattus) and mouse (Mus), by modeling inhalation (LC(50)) data. Multiple linear regression (MLR) models using the ordinary-least-squares (OLS) method, based on theoretical molecular descriptors selected by genetic algorithm (GA), were used for QSAR studies. Training and prediction sets were prepared a priori, and these sets were used to derive statistically robust and predictive (both internally and externally) models. The structural applicability domain (AD) of the model was verified on a larger set of per- and polyfluorinated chemicals retrieved from different databases and journals. The descriptors involved, the similarities, and the differences observed between models pertaining to the toxicity related to the two species are discussed. Chemometric methods such as principal component analysis (PCA) and multidimensional scaling (MDS) were used to select most toxic compounds from those within the AD of both models, which will be subjected to experimental tests

  20. Three-dimensional (3D) printed endovascular simulation models: a feasibility study

    PubMed Central

    Nesbitt, Craig; McCaslin, James; Bagnall, Alan; Davey, Philip; Bose, Pentop; Williams, Rob

    2017-01-01

    Background Three-dimensional (3D) printing is a manufacturing process in which an object is created by specialist printers designed to print in additive layers to create a 3D object. Whilst there are initial promising medical applications of 3D printing, a lack of evidence to support its use remains a barrier for larger scale adoption into clinical practice. Endovascular virtual reality (VR) simulation plays an important role in the safe training of future endovascular practitioners, but existing VR models have disadvantages including cost and accessibility which could be addressed with 3D printing. Methods This study sought to evaluate the feasibility of 3D printing an anatomically accurate human aorta for the purposes of endovascular training. Results A 3D printed model was successfully designed and printed and used for endovascular simulation. The stages of development and practical applications are described. Feedback from 96 physicians who answered a series of questions using a 5 point Likert scale is presented. Conclusions Initial data supports the value of 3D printed endovascular models although further educational validation is required. PMID:28251121

  1. Differentiating bladder carcinoma from bladder wall using 3D textural features: an initial study

    NASA Astrophysics Data System (ADS)

    Xu, Xiaopan; Zhang, Xi; Liu, Yang; Tian, Qiang; Zhang, Guopeng; Lu, Hongbing

    2016-03-01

    Differentiating bladder tumors from wall tissues is of critical importance for the detection of invasion depth and cancer staging. The textural features embedded in bladder images have demonstrated their potentials in carcinomas detection and classification. The purpose of this study was to investigate the feasibility of differentiating bladder carcinoma from bladder wall using three-dimensional (3D) textural features extracted from MR bladder images. The widely used 2D Tamura features were firstly wholly extended to 3D, and then different types of 3D textural features including 3D features derived from gray level co-occurrence matrices (GLCM) and grey level-gradient co-occurrence matrix (GLGCM), as well as 3D Tamura features, were extracted from 23 volumes of interest (VOIs) of bladder tumors and 23 VOIs of patients' bladder wall. Statistical results show that 30 out of 47 features are significantly different between cancer tissues and wall tissues. Using these features with significant differences between these two types of tissues, classification performance with a supported vector machine (SVM) classifier demonstrates that the combination of three types of selected 3D features outperform that of using only one type of features. All the observations demonstrate that significant textural differences exist between carcinomatous tissues and bladder wall, and 3D textural analysis may be an effective way for noninvasive staging of bladder cancer.

  2. Oxygen ingress study of 3D printed gaseous radiation detector enclosures

    SciTech Connect

    Steer, Christopher A.; Durose, Aaron

    2015-07-01

    As part of our ongoing studies into the potential application of 3D printing techniques to gaseous radiation detectors, we have studied the ability of 3D printed enclosures to resist environmental oxygen ingress. A set of cuboid and hexagonal prism shaped enclosures with wall thicknesses of 4 mm, 6 mm, 8 mm and 10 mm were designed and printed in nylon using a EOSINT P 730 Selective Laser Sintering 3D printer system These test enclosures provide a comparison of different environmental gas ingress for different 3D printing techniques. The rate of change of oxygen concentration was found to be linear, decreasing as the wall thickness increases. It was also found that the hexagonal prism geometry produced a lower rate of change of oxygen concentration compared with the cuboid shaped enclosures. Possible reasons as to why these results were obtained are discussed The implications for the this study for deployable systems are also discussed (authors)

  3. A study on radiative transfer effects in 3-D cloudy atmosphere using satellite data

    NASA Astrophysics Data System (ADS)

    Okata, M.; Nakajima, T.; Suzuki, K.; Inoue, T.; Nakajima, T. Y.; Okamoto, H.

    2017-01-01

    This study evaluates 3-D cloud effects on the radiation budget with a combined use of active sensor cloud profiling radar/CloudSat and imager Moderate Resolution Imaging Spectroradiometer/Aqua data on the A-train. An algorithm is devised for constructing 3-D cloud fields based on satellite-observed cloud information. The 3-D cloud fields thus constructed are used to calculate the broadband solar and thermal radiative fluxes with a 3-D radiative transfer code developed by the authors. The aim of this study is to investigate the effects of cloud morphology on solar radiative transfer in cloudy atmosphere. For this purpose, 3-D cloud fields are constructed with the new satellite-based method, to which full 3D-RT (radiative transfer) simulations are applied. The simulated 3-D radiation fields are then used to examine and quantify errors of existing typical plane-parallel approximations, i.e., Plane-Parallel Approximation, Independent Pixel Approximation and Tilted Independent Pixel Approximation. Such 3D-RT simulations also serve to address another objective of this study, i.e., to devise an accurate approximation and to characterize the observed specific 3D-RT effects by the cloud morphology based on knowledge of idealized 3D-RT effects. We introduce a modified approach based on an optimum value of diffusivity factor to better approximate the radiative fluxes for arbitrary solar zenith angle determined from the results of 3-D radiative transfer simulations to redeem the overcorrections of these approximations for large solar zenith angles (SZAs). This new approach, called Slant path Independent Pixel Approximation, is found to be better than other approximations when SZA is large for some cloud cases. Based on the SZA dependence of the errors of these approximations relative to 3-D computations, satellite-observed real cloud cases are found to fall into either of three types of different morphologies, i.e., isolated cloud type, upper cloud-roughened type and lower

  4. Comparison of 2D versus 3D mammography with screening cases: an observer study

    NASA Astrophysics Data System (ADS)

    Fernandez, James Reza; Deshpande, Ruchi; Hovanessian-Larsen, Linda; Liu, Brent

    2012-02-01

    Breast cancer is the most common type of non-skin cancer in women. 2D mammography is a screening tool to aid in the early detection of breast cancer, but has diagnostic limitations of overlapping tissues, especially in dense breasts. 3D mammography has the potential to improve detection outcomes by increasing specificity, and a new 3D screening tool with a 3D display for mammography aims to improve performance and efficiency as compared to 2D mammography. An observer study using human studies collected from was performed to compare traditional 2D mammography with this new 3D mammography technique. A prior study using a mammography phantom revealed no difference in calcification detection, but improved mass detection in 2D as compared to 3D. There was a significant decrease in reading time for masses, calcifications, and normals in 3D compared to 2D, however, as well as more favorable confidence levels in reading normal cases. Data for this current study is currently being obtained, and a full report should be available in the next few weeks.

  5. 3D current source density imaging based on acoustoelectric effect: a simulation study using unipolar pulses

    PubMed Central

    Yang, Renhuan; Li, Xu; Liu, Jun; He, Bin

    2011-01-01

    It is of importance to image electrical activity and properties of biological tissues. Recently hybrid imaging modality combing ultrasound scanning and source imaging through the acousto-electric (AE) effect has generated considerable interest. Such modality has the potential to provide high spatial resolution current density imaging by utilizing the pressure induced AE resistivity change confined at the ultrasound focus. In this study, we investigate a novel 3-dimensional (3D) ultrasound current source density imaging (UCSDI) approach using unipolar ultrasound pulses. Utilizing specially designed unipolar ultrasound pulses and by combining AE signals associated to the local resistivity changes at the focusing point, we are able to reconstruct the 3D current density distribution with the boundary voltage measurements obtained while performing a 3D ultrasound scan. We have shown in computer simulation that using the present method, it is feasible to image with high spatial resolution an arbitrary 3D current density distribution in an inhomogeneous conductive media. PMID:21628774

  6. Why 3D Cameras are Not Popular: A Qualitative User Study on Stereoscopic Photography Acceptance

    NASA Astrophysics Data System (ADS)

    Hakala, Jussi; Westman, Stina; Salmimaa, Marja; Pölönen, Monika; Järvenpää, Toni; Häkkinen, Jukka

    2014-03-01

    Digital stereoscopic 3D cameras have entered the consumer market in recent years, but the acceptance of this novel technology has not yet been studied. The aim of this study was to identify the benefits and problems that novice users encounter in 3D photography by equipping five users with 3D cameras for a 4-week trial. We gathered data using a weekly questionnaire, an exit interview, and a stereoscopic disparity analysis of the 699 photographs taken during the trial. The results indicate that the participants took photographs at too-close distances, which caused excessive disparities. They learned to avoid the problem to some extent; the number of failed photographs due to excessive stereoscopic disparity decreased 70 % in 4 weeks. The participants also developed a preference for subjects that included clear depth differences and started to avoid photographing people because they looked unnatural in 3D photographs. They also regarded flash-induced shadows and edge violations problematic because of the unnatural effects in the photographs. We propose in-camera assistance tools for 3D cameras to make 3D photography easier.

  7. Combinatorial QSAR Modeling of Rat Acute Toxicity by Oral Exposure

    EPA Science Inventory

    Quantitative Structure-Activity Relationship (QSAR) toxicity models have become popular tools for identifying potential toxic compounds and prioritizing candidates for animal toxicity tests. However, few QSAR studies have successfully modeled large, diverse mammalian toxicity end...

  8. The performance & flow visualization studies of three-dimensional (3-D) wind turbine blade models

    NASA Astrophysics Data System (ADS)

    Sutrisno, Prajitno, Purnomo, W., Setyawan B.

    2016-06-01

    Recently, studies on the design of 3-D wind turbine blades have a less attention even though 3-D blade products are widely sold. In contrary, advanced studies in 3-D helicopter blade tip have been studied rigorously. Studies in wind turbine blade modeling are mostly assumed that blade spanwise sections behave as independent two-dimensional airfoils, implying that there is no exchange of momentum in the spanwise direction. Moreover, flow visualization experiments are infrequently conducted. Therefore, a modeling study of wind turbine blade with visualization experiment is needed to be improved to obtain a better understanding. The purpose of this study is to investigate the performance of 3-D wind turbine blade models with backward-forward swept and verify the flow patterns using flow visualization. In this research, the blade models are constructed based on the twist and chord distributions following Schmitz's formula. Forward and backward swept are added to the rotating blades. Based on this, the additional swept would enhance or diminish outward flow disturbance or stall development propagation on the spanwise blade surfaces to give better blade design. Some combinations, i. e., b lades with backward swept, provide a better 3-D favorable rotational force of the rotor system. The performance of the 3-D wind turbine system model is measured by a torque meter, employing Prony's braking system. Furthermore, the 3-D flow patterns around the rotating blade models are investigated by applying "tuft-visualization technique", to study the appearance of laminar, separated, and boundary layer flow patterns surrounding the 3-dimentional blade system.

  9. Rationalizing fragment based drug discovery for BACE1: insights from FB-QSAR, FB-QSSR, multi objective (MO-QSPR) and MIF studies

    NASA Astrophysics Data System (ADS)

    Manoharan, Prabu; Vijayan, R. S. K.; Ghoshal, Nanda

    2010-10-01

    The ability to identify fragments that interact with a biological target is a key step in FBDD. To date, the concept of fragment based drug design (FBDD) is increasingly driven by bio-physical methods. To expand the boundaries of QSAR paradigm, and to rationalize FBDD using In silico approach, we propose a fragment based QSAR methodology referred here in as FB-QSAR. The FB-QSAR methodology was validated on a dataset consisting of 52 Hydroxy ethylamine (HEA) inhibitors, disclosed by GlaxoSmithKline Pharmaceuticals as potential anti-Alzheimer agents. To address the issue of target selectivity, a major confounding factor in the development of selective BACE1 inhibitors, FB-QSSR models were developed using the reported off target activity values. A heat map constructed, based on the activity and selectivity profile of the individual R-group fragments, and was in turn used to identify superior R-group fragments. Further, simultaneous optimization of multiple properties, an issue encountered in real-world drug discovery scenario, and often overlooked in QSAR approaches, was addressed using a Multi Objective (MO-QSPR) method that balances properties, based on the defined objectives. MO-QSPR was implemented using Derringer and Suich desirability algorithm to identify the optimal level of independent variables ( X) that could confer a trade-off between selectivity and activity. The results obtained from FB-QSAR were further substantiated using MIF (Molecular Interaction Fields) studies. To exemplify the potentials of FB-QSAR and MO-QSPR in a pragmatic fashion, the insights gleaned from the MO-QSPR study was reverse engineered using Inverse-QSAR in a combinatorial fashion to enumerate some prospective novel, potent and selective BACE1 inhibitors.

  10. Rapid prototyping for tissue-engineered bone scaffold by 3D printing and biocompatibility study

    PubMed Central

    He, Hui-Yu; Zhang, Jia-Yu; Mi, Xue; Hu, Yang; Gu, Xiao-Yu

    2015-01-01

    The prototyping of tissue-engineered bone scaffold (calcined goat spongy bone-biphasic ceramic composite/PVA gel) by 3D printing was performed, and the biocompatibility of the fabricated bone scaffold was studied. Pre-designed STL file was imported into the GXYZ303010-XYLE 3D printing system, and the tissue-engineered bone scaffold was fabricated by 3D printing using gel extrusion. Rabbit bone marrow stromal cells (BMSCs) were cultured in vitro and then inoculated to the sterilized bone scaffold obtained by 3D printing. The growth of rabbit BMSCs on the bone scaffold was observed under the scanning electron microscope (SEM). The effect of the tissue-engineered bone scaffold on the proliferation and differentiation of rabbit BMSCs using MTT assay. Universal testing machine was adopted to test the tensile strength of the bone scaffold. The leachate of the bone scaffold was prepared and injected into the New Zealand rabbits. Cytotoxicity test, acute toxicity test, pyrogenic test and intracutaneous stimulation test were performed to assess the biocompatibility of the bone scaffold. Bone scaffold manufactured by 3D printing had uniform pore size with the porosity of about 68.3%. The pores were well interconnected, and the bone scaffold showed excellent mechanical property. Rabbit BMSCs grew and proliferated on the surface of the bone scaffold after adherence. MTT assay indicated that the proliferation and differentiation of rabbit BMSCs on the bone scaffold did not differ significantly from that of the cells in the control. In vivo experiments proved that the bone scaffold fabricated by 3D printing had no acute toxicity, pyrogenic reaction or stimulation. Bone scaffold manufactured by 3D printing allows the rabbit BMSCs to adhere, grow and proliferate and exhibits excellent biomechanical property and high biocompatibility. 3D printing has a good application prospect in the prototyping of tissue-engineered bone scaffold. PMID:26380018

  11. Rapid prototyping for tissue-engineered bone scaffold by 3D printing and biocompatibility study.

    PubMed

    He, Hui-Yu; Zhang, Jia-Yu; Mi, Xue; Hu, Yang; Gu, Xiao-Yu

    2015-01-01

    The prototyping of tissue-engineered bone scaffold (calcined goat spongy bone-biphasic ceramic composite/PVA gel) by 3D printing was performed, and the biocompatibility of the fabricated bone scaffold was studied. Pre-designed STL file was imported into the GXYZ303010-XYLE 3D printing system, and the tissue-engineered bone scaffold was fabricated by 3D printing using gel extrusion. Rabbit bone marrow stromal cells (BMSCs) were cultured in vitro and then inoculated to the sterilized bone scaffold obtained by 3D printing. The growth of rabbit BMSCs on the bone scaffold was observed under the scanning electron microscope (SEM). The effect of the tissue-engineered bone scaffold on the proliferation and differentiation of rabbit BMSCs using MTT assay. Universal testing machine was adopted to test the tensile strength of the bone scaffold. The leachate of the bone scaffold was prepared and injected into the New Zealand rabbits. Cytotoxicity test, acute toxicity test, pyrogenic test and intracutaneous stimulation test were performed to assess the biocompatibility of the bone scaffold. Bone scaffold manufactured by 3D printing had uniform pore size with the porosity of about 68.3%. The pores were well interconnected, and the bone scaffold showed excellent mechanical property. Rabbit BMSCs grew and proliferated on the surface of the bone scaffold after adherence. MTT assay indicated that the proliferation and differentiation of rabbit BMSCs on the bone scaffold did not differ significantly from that of the cells in the control. In vivo experiments proved that the bone scaffold fabricated by 3D printing had no acute toxicity, pyrogenic reaction or stimulation. Bone scaffold manufactured by 3D printing allows the rabbit BMSCs to adhere, grow and proliferate and exhibits excellent biomechanical property and high biocompatibility. 3D printing has a good application prospect in the prototyping of tissue-engineered bone scaffold.

  12. Exploring QSAR, pharmacophore mapping and docking studies and virtual library generation for cycloguanil derivatives as PfDHFR-TS inhibitors.

    PubMed

    Ojha, Probir Kumar; Roy, Kunal

    2011-05-01

    Resistance of available antimalarial drugs against Plasmodium species is one of the major problems of malaria control in the developing world. In the present study, we have performed QSAR, pharmacophore mapping and molecular docking studies of cycloguanil derivatives as Plasmodium falciparum dihydrofolate reductase thymidylate synthase (PfDHFR-TS) inhibitors to explore essential features required for the antimalarial activity and important interaction patterns between the enzyme and ligands for the design of new potent PfDHFR-TS inhibitors. The QSAR studies have been carried out using topological parameters along with thermodynamic and structural descriptors. Acceptable values of internal and external validation parameters for the developed QSAR models confirm acceptability of the models. Pharmacophore mapping revealed that two hydrogen bond donor (HBD) features and a hydrophobic feature (HYD) are important parameters for PfDHFR-TS inhibitory activity. The docking studies suggest that the PfDHFR-TS inhibitors interact with Asp54, Ile14, Ile164, ser108, Ser111, Tyr170, Met55, Ala16, Thr185, Leu46, Cys15, Phe58, Ile112, Trp48, Tyr57 and Leu119 amino acid residues. The QSAR, pharmacophore and docking studies inferred that i) branching of the substituents at R1 and R2 positions should be less (small alkyl chain substituents are favored); ii) the electronegativity of the molecules should be high but within some limit; iii) the size and volume of the molecules should be high; iv) molecules should be flexible enough; v) R configuration at C6 position of the triazine ring favors the inhibitory binding affinity; vi) the substituents of the phenyl ring at 3, 4 and 5 position of the phenyl ring should be small hydrophobic groups. Based on these studies, we have designed a library of cycloguanil derivatives with good in silico predicted PfDHFR-TS inhibitory activity.

  13. Protein-protein interaction networks studies and importance of 3D structure knowledge.

    PubMed

    Lu, Hui-Chun; Fornili, Arianna; Fraternali, Franca

    2013-12-01

    Protein-protein interaction networks (PPINs) are a powerful tool to study biological processes in living cells. In this review, we present the progress of PPIN studies from abstract to more detailed representations. We will focus on 3D interactome networks, which offer detailed information at the atomic level. This information can be exploited in understanding not only the underlying cellular mechanisms, but also how human variants and disease-causing mutations affect protein functions and complexes' stability. Recent studies have used structural information on PPINs to also understand the molecular mechanisms of binding partner selection. We will address the challenges in generating 3D PPINs due to the restricted number of solved protein structures. Finally, some of the current use of 3D PPINs will be discussed, highlighting their contribution to the studies in genotype-phenotype relationships and in the optimization of targeted studies to design novel chemical compounds for medical treatments.

  14. Mitral valve analysis using a novel 3D holographic display: a feasibility study of 3D ultrasound data converted to a holographic screen.

    PubMed

    Beitnes, Jan Otto; Klæboe, Lars Gunnar; Karlsen, Jørn Skaarud; Urheim, Stig

    2015-02-01

    The aim of the present study was to test the feasibility of analyzing 3D ultrasound data on a novel holographic display. An increasing number of mini-invasive procedures for mitral valve repair require more effective visualization to improve patient safety and speed of procedures. A novel 3D holographic display has been developed and may have the potential to guide interventional cardiac procedures in the near future. Forty patients with degenerative mitral valve disease were analyzed. All had complete 2D transthoracic (TTE) and transoesophageal (TEE) echocardiographic examinations. In addition, 3D TTE of the mitral valve was obtained and recordings were converted from the echo machine to the holographic screen. Visual inspection of the mitral valve during surgery or TEE served as the gold standard. 240 segments were analyzed by 2 independent observers. A total of 53 segments were prolapsing. The majority included P2 (31), the remaining located at A2 (8), A3 (6), P3 (5), P1 (2) and A1 (1). The sensitivity and specificity of the 3D display was 87 and 99 %, respectively (observer I), and for observer II 85 and 97 %, respectively. The accuracies and precisions were 96.7 and 97.9 %, respectively, (observer I), 94.3 and 88.2 % (observer II), and inter-observer agreement was 0.954 with Cohen's Kappa 0.86. We were able to convert 3D ultrasound data to the holographic display. A very high accuracy and precision was shown, demonstrating the feasibility of analyzing 3D echo of the mitral valve on the holographic screen.

  15. Anabolic and androgenic activities of 19-nor-testosterone steroids: QSAR study using quantum and physicochemical molecular descriptors.

    PubMed

    Alvarez-Ginarte, Yoanna María; Montero-Cabrera, Luis Alberto; de la Vega, José Manuel García; Noheda-Marín, Pedro; Marrero-Ponce, Yovani; Ruíz-García, José Alberto

    2011-08-01

    Quantitative structure-activity relationship (QSAR) study of 19-nor-testosterone steroids family was performed using quantum and physicochemical molecular descriptors. The quantum-chemical descriptors were calculated using semiempirical calculations. The descriptor values were statistically correlated using multi-linear regression analysis. The QSAR study indicated that the electronic properties of these derivatives have significant relationship with observed biological activities. The found QSAR equations explain that the energy difference between the LUMO and HOMO, the total dipole moment, the chemical potential and the value of the net charge of different carbon atoms in the steroid nucleus showed key interaction of these steroids with their anabolic-androgenic receptor binding site. The calculated values predict that the 17α-cyclopropyl-17β, 3β-hydroxy-4-estrene compound presents the highest anabolic-androgenic ratio (AAR) and the 7α-methyl-17β-acetoxy-estr-4-en-3-one compound the lowest AAR. This study might be helpful in the future successful identification of "real" or "virtual" anabolic-androgenic steroids.

  16. Cancer Cytokines and the Relevance of 3D Cultures for Studying those Implicated in Human Cancers.

    PubMed

    Maddaly, Ravi; Subramaniyan, Aishwarya; Balasubramanian, Harini

    2017-03-06

    Cancers are complex conditions and involving several factors for oncogenesis and progression. Of the various factors influencing the physiology of cancers, cytokines are known to play significant roles as mediators of functions. Intricate cytokine networks have been identified in cancers and interest in cytokines associated with cancers has been gaining ground. Of late, some of these cytokines are even identified as potential targets for cancer therapy apart from a few others such as IL-6 being identified as markers for disease prognosis. Of the major contributors to cancer research, cancer cell lines occupy the top slot as the most widely used material in vitro. In vitro cell cultures have seen significant evolution by the introduction of 3 dimensional (3D) culture systems. 3D cell cultures are now widely accepted as excellent material for cancer research which surpasses the traditional monolayer cultures. Cancer research has benefitted from 3D cell cultures for understanding the various hallmarks of cancers. However, the potential of these culture systems are still unexploited for cancer cytokine research compared to the other aspects of cancers such as gene expression changes, drug-induced toxicity, morphology, angiogenesis and invasion. Considering the importance of cancer cytokines, 3D cell cultures can be better utilized in understanding their roles and functions. Some of the possibilities where 3D cell cultures can contribute to cancer cytokine research arise from the distinct morphology of the tumor spheroids, the extracellular matrix (ECM), and the spontaneous occurrence of nutrient and oxygen gradients. Also, the 3D culture models enable one to co-culture different types of cells as a simulation of in vivo conditions, enhancing their utility to study cancer cytokines. We review here the cancer associated cytokines the contributions of 3D cancer cell cultures for studying cancer cytokines. This article is protected by copyright. All rights reserved.

  17. Application of 3D photo-reconstruction in soil erosion studies

    NASA Astrophysics Data System (ADS)

    Castillo, Carlos; James, Michael; Pérez, Rafael; Gómez, Jose Alfonso

    2014-05-01

    3D photo-reconstruction (3D-PR) has been applied successfully to obtain elevation models using uncalibrated and nonmetric cameras for a range of geoscience applications (e.g. James and Robson, 2012), including gully erosion assessment (Castillo et al., 2012). However, its application in soil erosion studies is currently at the outset. The aim of this work is to compare 3D-PR with conventional techniques that have been employed traditionally for different purposes in soil erosion studies. In this preliminary work, we tested three applications that involve volume calculations: estimation of soil bulk density (BD), quantification of soil erosion at road banks (RB) and sedimentation rates behind check dams (CD). For each analysis, a PR field survey was carried out simultaneously with a conventional method (volume of water was used for BD, and total station surveys for RB and CD). For the 3D-PR technique, the accuracy as a function of the number of pictures taken was evaluated. In this study we explore the difference in the volume estimates between 3D-PR and conventional techniques as well as the time requirements for each method in order to compare their performance and optimal field of application.

  18. Structure–activity relationships study of mTOR kinase inhibition using QSAR and structure-based drug design approaches

    PubMed Central

    Lakhlili, Wiame; Yasri, Abdelaziz; Ibrahimi, Azeddine

    2016-01-01

    The discovery of clinically relevant inhibitors of mammalian target of rapamycin (mTOR) for anticancer therapy has proved to be a challenging task. The quantitative structure–activity relationship (QSAR) approach is a very useful and widespread technique for ligand-based drug design, which can be used to identify novel and potent mTOR inhibitors. In this study, we performed two-dimensional QSAR tests, and molecular docking validation tests of a series of mTOR ATP-competitive inhibitors to elucidate their structural properties associated with their activity. The QSAR tests were performed using partial least square method with a correlation coefficient of r2=0.799 and a cross-validation of q2=0.714. The chemical library screening was done by associating ligand-based to structure-based approach using the three-dimensional structure of mTOR developed by homology modeling. We were able to select 22 compounds from two databases as inhibitors of the mTOR kinase active site. We believe that the method and applications highlighted in this study will help future efforts toward the design of selective ATP-competitive inhibitors. PMID:27980424

  19. Computational study of 3-D hot-spot initiation in shocked insensitive high-explosive

    NASA Astrophysics Data System (ADS)

    Najjar, F. M.; Howard, W. M.; Fried, L. E.; Manaa, M. R.; Nichols, A., III; Levesque, G.

    2012-03-01

    High-explosive (HE) material consists of large-sized grains with micron-sized embedded impurities and pores. Under various mechanical/thermal insults, these pores collapse generating hightemperature regions leading to ignition. A hydrodynamic study has been performed to investigate the mechanisms of pore collapse and hot spot initiation in TATB crystals, employing a multiphysics code, ALE3D, coupled to the chemistry module, Cheetah. This computational study includes reactive dynamics. Two-dimensional high-resolution large-scale meso-scale simulations have been performed. The parameter space is systematically studied by considering various shock strengths, pore diameters and multiple pore configurations. Preliminary 3-D simulations are undertaken to quantify the 3-D dynamics.

  20. Comparative studies on gravisensitive protists on ground (2D and 3D clinostats) and in microgravity

    NASA Astrophysics Data System (ADS)

    Hemmersbach, Ruth; Strauch, Sebastian M.; Seibt, Dieter; Schuber, Marianne

    2006-09-01

    In order to prepare and support space experiments, 2D and 3D clinostats are widely applied to study the influence of simulated weightlessness on biological systems. In order to evaluate the results a comparison between the data obtained in simulation experiments and in real microgravity is necessary. We are currently analyzing the gravity-dependent behavior of the protists Paramecium biaurelia (ciliate) and Euglena gracilis (photosynthetic flagellate) on these different experimental platforms. So far, first results are presented concerning the behaviour of Euglena on a 2D fast rotating clinostat and a 3D clinostat as well as under real microgravity conditions (TEXUS sounding rocket flight), of Paramecium on a 2D clinostat and in microgravity. Our data show similar results during 2D and 3D clinorotation compared to real microgravity with respect to loss of orientation (gravitaxis) of Paramecium and Euglena and a decrease of linearity of the cell tracks of Euglena. However, the increase of the mean swimming velocities, especially during 3D clinorotation (Euglena) and 2D clinorotation of Paramecium might indicate a persisting mechanostimulation of the cells. Further studies including long-term 2D and 3D clinostat exposition will enable us to demonstrate the qualification of the applied simulation methods.

  1. Model studies of blood flow in basilar artery with 3D laser Doppler anemometer

    NASA Astrophysics Data System (ADS)

    Frolov, S. V.; Sindeev, S. V.; Liepsch, D.; Balasso, A.; Proskurin, S. G.; Potlov, A. Y.

    2015-03-01

    It is proposed an integrated approach to the study of basilar artery blood flow using 3D laser Doppler anemometer for identifying the causes of the formation and development of cerebral aneurysms. Feature of the work is the combined usage of both mathematical modeling and experimental methods. Described the experimental setup and the method of measurement of basilar artery blood flow, carried out in an interdisciplinary laboratory of Hospital Rechts der Isar of Technical University of Munich. The experimental setup used to simulate the blood flow in the basilar artery and to measure blood flow characteristics using 3D laser Doppler anemometer (3D LDA). Described a method of numerical studies carried out in Tambov State Technical University and the Bakoulev Center for Cardiovascular Surgery. Proposed an approach for sharing experimental and numerical methods of research to identify the causes of the basilar artery aneurysms.

  2. Studies of the 3D Structure of the Nucleon at Jlab

    SciTech Connect

    Avakian, Harut

    2016-07-01

    Studies of the 3D structure of the nucleon encoded in Transverse Momentum Dependent distribution and fragmentation functions of partons and Generalized Parton Distributions are among the key objectives of the JLab 12 GeV upgrade and the Electron Ion Collider. Main challenges in extracting 3D partonic distributions from precision measurements of hard scattering processes include clear understanding of leading twist QCD fundamentals, higher twist effects, and also correlations of hadron production in target and current fragmentation regions. In this contribution we discuss some ongoing studies and future measurements of spin-orbit correlations at Jefferson Lab.

  3. Data compression studies for NOAA Hyperspectral Environmental Suite (HES) using 3D integer wavelet transforms with 3D set partitioning in hierarchical trees

    NASA Astrophysics Data System (ADS)

    Huang, Bormin; Huang, Hung-Lung; Chen, Hao; Ahuja, Alok; Baggett, Kevin; Schmit, Timothy J.; Heymann, Roger W.

    2004-02-01

    The next-generation NOAA/NESDIS GOES-R hyperspectral sounder, now referred to as the HES (Hyperspectral Environmental Suite), will have hyperspectral resolution (over one thousand channels with spectral widths on the order of 0.5 wavenumber) and high spatial resolution (less than 10 km). Hyperspectral sounder data is a particular class of data requiring high accuracy for useful retrieval of atmospheric temperature and moisture profiles, surface characteristics, cloud properties, and trace gas information. Hence compression of these data sets is better to be lossless or near lossless. Given the large volume of three-dimensional hyperspectral sounder data that will be generated by the HES instrument, the use of robust data compression techniques will be beneficial to data transfer and archive. In this paper, we study lossless data compression for the HES using 3D integer wavelet transforms via the lifting schemes. The wavelet coefficients are processed with the 3D set partitioning in hierarchical trees (SPIHT) scheme followed by context-based arithmetic coding. SPIHT provides better coding efficiency than Shapiro's original embedded zerotree wavelet (EZW) algorithm. We extend the 3D SPIHT scheme to take on any size of 3D satellite data, each of whose dimensions need not be divisible by 2N, where N is the levels of the wavelet decomposition being performed. The compression ratios of various kinds of wavelet transforms are presented along with a comparison with the JPEG2000 codec.

  4. Lossless data compression studies for NOAA hyperspectral environmental suite using 3D integer wavelet transforms with 3D embedded zerotree coding

    NASA Astrophysics Data System (ADS)

    Huang, Bormin; Huang, Hung-Lung; Chen, Hao; Ahuja, Alok; Baggett, Kevin; Schmit, Timothy J.; Heymann, Roger W.

    2003-09-01

    Hyperspectral sounder data is a particular class of data that requires high accuracy for useful retrieval of atmospheric temperature and moisture profiles, surface characteristics, cloud properties, and trace gas information. Therefore compression of these data sets is better to be lossless or near lossless. The next-generation NOAA/NESDIS GOES-R hyperspectral sounder, now referred to as the HES (Hyperspectral Environmental Suite), will have hyperspectral resolution (over one thousand channels with spectral widths on the order of 0.5 wavenumber) and high spatial resolution (less than 10 km). Given the large volume of three-dimensional hyperspectral sounder data that will be generated by the HES instrument, the use of robust data compression techniques will be beneficial to data transfer and archive. In this paper, we study lossless data compression for the HES using 3D integer wavelet transforms via the lifting schemes. The wavelet coefficients are then processed with the 3D embedded zerotree wavelet (EZW) algorithm followed by context-based arithmetic coding. We extend the 3D EZW scheme to take on any size of 3D satellite data, each of whose dimensions need not be divisible by 2N, where N is the levels of the wavelet decomposition being performed. The compression ratios of various kinds of wavelet transforms are presented along with a comparison with the JPEG2000 codec.

  5. Carboxy-Methyl-Cellulose (CMC) hydrogel-filled 3-D scaffold: Preliminary study through a 3-D antiproliferative activity of Centella asiatica extract

    NASA Astrophysics Data System (ADS)

    Aizad, Syazwan; Yahaya, Badrul Hisham; Zubairi, Saiful Irwan

    2015-09-01

    This study focuses on the effects of using the water extract from Centella asiatica on the mortality of human lung cancer cells (A549) with the use of novel 3-D scaffolds infused with CMC hydrogel. A biodegradable polymer, poly (hydroxybutyrate-co-hydroxyvalerate) (PHBV) was used in this study as 3-D scaffolds, with some modifications made by introducing the gel structure on its pore, which provides a great biomimetic microenvironment for cells to grow apart from increasing the interaction between the cells and cell-bioactive extracts. The CMC showed a good hydrophilic characteristic with mean contact angle of 24.30 ± 22.03°. To ensure the CMC gel had good attachments with the scaffolds, a surface treatment was made before the CMC gel was infused into the scaffolds. The results showed that these modified scaffolds contained 42.41 ± 0.14% w/w of CMC gel, which indicated that the gel had already filled up the entire pore of 3-D scaffolds. Besides, the infused hydrogel scaffolds took only 24 hours to be saturated when absorbing the water. The viability of cancer cells by MTS assay after being treated with Centella asiatica showed that the scaffolds infused with CMC hydrogel had the cell viability of 46.89 ± 1.20% followed by porous 3-D model with 57.30 ± 1.60% of cell viability, and the 2-D model with 67.10 ± 1.10% of cell viability. The inhibitory activity in cell viability between 2-D and 3-D models did not differ significantly (p>0.05) due to the limitation of time in incubating the extract with the cell in the 3-D model microenvironment. In conclusion, with the application of 3-D scaffolds infused with CMC hydrogel, the extracts of Centella asiatica has been proven to have the ability to kill cancer cells and have a great potential to become one of the alternative methods in treating cancer patients.

  6. PRESAGETM - Development and optimization studies of a 3D radiochromic plastic dosimeter - Part 1

    NASA Astrophysics Data System (ADS)

    Adamovics, J.; Jordan, K.; Dietrich, J.

    2006-12-01

    This paper studies the polymerization of six different transparent plastics as potential 3D dosimeter matrices. In addition, six different leuco dyes and sixteen different free radical initiators were evaluated. Finally, the photoreactivity of the dosimeter was studied so that the effect of exposure to UV could be minimized.

  7. Best Practices for Designing Online Learning Environments for 3D Modeling Curricula: A Delphi Study

    ERIC Educational Resources Information Center

    Mapson, Kathleen Harrell

    2011-01-01

    The purpose of this study was to develop an inventory of best practices for designing online learning environments for 3D modeling curricula. Due to the instructional complexity of three-dimensional modeling, few have sought to develop this type of course for online teaching and learning. Considering this, the study aimed to collectively aggregate…

  8. Design, synthesis, α-glucosidase inhibitory activity, molecular docking and QSAR studies of benzimidazole derivatives

    NASA Astrophysics Data System (ADS)

    Dinparast, Leila; Valizadeh, Hassan; Bahadori, Mir Babak; Soltani, Somaieh; Asghari, Behvar; Rashidi, Mohammad-Reza

    2016-06-01

    In this study the green, one-pot, solvent-free and selective synthesis of benzimidazole derivatives is reported. The reactions were catalyzed by ZnO/MgO containing ZnO nanoparticles as a highly effective, non-toxic and environmentally friendly catalyst. The structure of synthesized benzimidazoles was characterized using spectroscopic technics (FT-IR, 1HNMR, 13CNMR). Synthesized compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 3c, 3e, 3l and 4n were potent inhibitors with IC50 values ranging from 60.7 to 168.4 μM. In silico studies were performed to explore the binding modes and interactions between enzyme and synthesized benzimidazoles. Developed linear QSAR model based on density and molecular weight could predict bioactivity of newly synthesized compounds well. Molecular docking studies revealed the availability of some hydrophobic interactions. In addition, the bioactivity of most potent compounds had good correlation with estimated free energy of binding (ΔGbinding) which was calculated according to docked best conformations.

  9. 3D electrical structure of porphyry copper deposit: A case study of Shaxi copper deposit

    NASA Astrophysics Data System (ADS)

    Chen, Xiang-Bin; Lü, Qing-Tian; Yan, Jia-Yong

    2012-06-01

    Located in Lu-Zong ore concentration area, middle-lower Yangtze metallogenic belt, ShaXi porphyry copper deposit is a typical hydrothermal deposit. To investigate the distribution of deep ore bodies and spatial characteristics of host structures, an AMT survey was conducted in mining area. Eighteen pseudo-2D resistivity sections were constructed through careful processing and inversion. These sections clearly show resistivity difference between the Silurian sandstones formation and quartz diorite porphyry and this porphyry copper formation was controlled by the highly resistive anticlines. Using 3D block Kriging interpolation method and 3D visualization techniques, we constructed a detailed 3D resistivity model of quartz diorite porphyry which shows the shape and spatial distribution of deep ore bodies. This case study can serve as a good example for future ore prospecting in and around this mining area.

  10. A Survey Study of the Blast Furnace at Kuangshan Village Using 3D Laser Scanning

    NASA Astrophysics Data System (ADS)

    Wang, Jin; Huang, Xing; Qian, Wei

    2017-01-01

    The blast furnace from the Northern Song Dynasty at Kuangshan Village is the tallest blast furnace that remains from ancient China. Previous studies have assumed that the furnace had a closed mouth. In this paper, a three-dimensional (3D) model of the blast furnace is constructed using 3D laser scanning technology, and accurate profile data are obtained using software. It is shown that the furnace throat is smaller than had been previously thought and that the furnace mouth is of the open type. This new furnace profile constitutes a discovery in the history of iron-smelting technology.

  11. 3D evaluation of palatal rugae for human identification using digital study models

    PubMed Central

    Taneva, Emilia D.; Johnson, Andrew; Viana, Grace; Evans, Carla A.

    2015-01-01

    Background: While there is literature suggesting that the palatal rugae could be used for human identification, most of these studies use two-dimensional (2D) approach. Aim: The aims of this study were to evaluate palatal ruga patterns using three-dimensional (3D) digital models; compare the most clinically relevant digital model conversion techniques for identification of the palatal rugae; develop a protocol for overlay registration; determine changes in palatal ruga individual patterns through time; and investigate the efficiency and accuracy of 3D matching processes between different individuals’ patterns. Material and Methods: Five cross sections in the anteroposterior dimension and four cross sections in the transverse dimension were computed which generated 18 2D variables. In addition, 13 3D variables were defined: The posterior point of incisive papilla (IP), and the most medial and lateral end points of the palatal rugae (R1MR, R1ML, R1LR, R1LL, R2MR, R2ML, R2LR, R2LL, R3MR, R3ML, R3LR, and R3LL). The deviation magnitude for each variable was statistically analyzed in this study. Five different data sets with the same 31 landmarks were evaluated in this study. Results: The results demonstrated that 2D images and linear measurements in the anteroposterior and transverse dimensions were not sufficient for comparing different digital model conversion techniques using the palatal rugae. 3D digital models proved to be a highly effective tool in evaluating different palatal ruga patterns. The 3D landmarks showed no statistically significant mean differences over time or as a result of orthodontic treatment. No statistically significant mean differences were found between different digital model conversion techniques, that is, between OrthoCAD™ and Ortho Insight 3D™, and between Ortho Insight 3D™ and the iTero® scans, when using 12 3D palatal rugae landmarks for comparison. Conclusion: Although 12 palatal 3D landmarks could be used for human

  12. Paper/PMMA Hybrid 3D Cell Culture Microfluidic Platform for the Study of Cellular Crosstalk.

    PubMed

    Lei, Kin Fong; Chang, Chih-Hsuan; Chen, Ming-Jie

    2017-04-06

    Studying cellular crosstalk is important for understanding tumor initiation, progression, metastasis, and therapeutic resistance. Moreover, a three-dimensional (3D) cell culture model can provide a more physiologically meaningful culture microenvironment. However, studying cellular crosstalk in a 3D cell culture model involves tedious processing. In this study, a paper/poly(methyl methacrylate) (PMMA) hybrid 3D cell culture microfluidic platform was successfully developed for the study of cellular crosstalk. The platform was a paper substrate with culture microreactors placed on a PMMA substrate with hydrogel-infused channels. Different types of cells were directly seeded and cultured in the microreactors. Aberrant cell proliferation of the affected cells was induced by secretions from transfected cells, and the proliferation ratios were investigated using a colorimetric method. The results showed that the responses of cellular crosstalk were different in different types of cells. Moreover, neutralizing and competitive assays were performed to show the functionality of the platform. Additionally, the triggered signaling pathways of the affected cells were directly analyzed by a subsequent immunoassay. The microfluidic platform provides a simple method for studying cellular crosstalk and the corresponding signaling pathways in a 3D culture model.

  13. Discovery of potent NEK2 inhibitors as potential anticancer agents using structure-based exploration of NEK2 pharmacophoric space coupled with QSAR analyses.

    PubMed

    Khanfar, Mohammad A; Banat, Fahmy; Alabed, Shada; Alqtaishat, Saja

    2017-02-01

    High expression of Nek2 has been detected in several types of cancer and it represents a novel target for human cancer. In the current study, structure-based pharmacophore modeling combined with multiple linear regression (MLR)-based QSAR analyses was applied to disclose the structural requirements for NEK2 inhibition. Generated pharmacophoric models were initially validated with receiver operating characteristic (ROC) curve, and optimum models were subsequently implemented in QSAR modeling with other physiochemical descriptors. QSAR-selected models were implied as 3D search filters to mine the National Cancer Institute (NCI) database for novel NEK2 inhibitors, whereas the associated QSAR model prioritized the bioactivities of captured hits for in vitro evaluation. Experimental validation identified several potent NEK2 inhibitors of novel structural scaffolds. The most potent captured hit exhibited an [Formula: see text] value of 237 nM.

  14. 3-D Magnetotelluric studies of Pre-Cambrian basement beneath southern Alberta

    NASA Astrophysics Data System (ADS)

    Nieuwenhuis, G.; Unsworth, M.; Pana, D.; Craven, J.

    2012-12-01

    The Pre-Cambrian basement rocks beneath Alberta record the tectonic events that led to the assembly of Laurentia in the Proterozoic. Since these rocks are covered with younger sedimentary rocks, they must be investigated with geophysical methods. In the 1990s, these basement rocks were studied with a number of long-period magnetotelluric (MT) profiles collected by the Lithoprobe project. Dimensionality analysis of these data show that they appear to be two dimensional (2-D) in the period band 1-1000 s. However 2-D inversion models were unable to reproduce these MT data with a realistic resistivity model. The inversion models were very rough and characterized by many closely spaced conductors. Since the Lithoprobe data gave indications of 3-D resistivity structure, especially in the Archean Loverna block, additional MT data were collected by the University of Alberta from 2006-2010 using NIMS instruments. The goal was to develop an array that would constrain a fully 3-D model of crustal and upper mantle resistivity. The data at periods 1-10,000 s were inverted using a 3-D inversion algorithm. Comparisons between 2-D and 3-D inversions show that both models fit the measured MT data equally well. The 3-D model shows that the structure is dominated by an upper mantle conductor beneath the Loverna Block (the Loverna conductor). This conductor was previously imaged by the 2-D inversion of the Lithoprobe data. Our 3-D model shows that the Loverna conductor extends throughout the Archean Loverna block (part of the Hearne Domain) and is bounded to the south by a potential field anomaly known as the Vulcan Structure. Initial interpretations of the Vulcan Structure explained it as an intracontinental rift zone, while more recent studies show that it is more likely a north dipping subduction zone between two Archean blocks. This interpretation is supported by our 3-D resistivity model, which shows a good correlation between north dipping reflectors and the top of conductivity

  15. Impact of 3D root uptake on solute transport: a numerical study

    NASA Astrophysics Data System (ADS)

    Schröder, N.; Javaux, M.; Vanderborght, J.; Steffen, B.; Vereecken, H.

    2011-12-01

    Plant transpiration is an important component of the hydrological cycle. Through root water uptake, plants do not only affect the 3D soil water flow velocity distribution, but also solute movement in soil. This numerical study aims at investigating how solute fate is impacted by root uptake using the 3D biophysical model R-SWMS (Javaux et al., 2008). This model solves the Richards equation in 3D in the soil and the flow equation within the plant root xylem vessels. Furthermore, for solute transport simulations, the 3D particle tracker PARTRACE (Bechtold et al., 2011) was used. . We generated 3D virtual steady-state breakthrough curves (BTC) experiments in soils with transpiring plants. The averaged BTCs were then fitted with a 1D numerical flow model under steady-state conditions to obtain apparent CDE parameters. Two types of root architecture, a fibrous and a taprooted structure, were compared in virtual 3D experiments. The solute uptake type or the transpiration rate were also modified and we analyzed how these parameters affected apparent disperisivity and velocity profiles. Our simulation results show, that both, apparent velocity and dispersivity length are affected by water and solute root uptake. In addition, under high exclusion processes (slight or no active uptake), solute accumulates around roots and generates a long tailing to the breakthrough curves, which cannot be reproduced by 1D models that simulate root water uptake with solute exclusion. This observation may have an important impact on how to model pollutant mass transfer to groundwater at larger scales. Javaux, M., T. Schröder, J. Vanderborght, and H. Vereecken. 2008. Use of a three-dimensional detailed modeling approach for predicting root water uptake. Vadose Zone J. 7:1079-1088.doi: 10.2136/vzj2007.0115. Bechtold, M., S. Haber-Pohlmeier, J. Vanderborght, A. Pohlmeier, P.A. Ferre, and H. Vereecken. 2011. Near-surface solute redistribution during evaporation. Submitted to Geophys. Res. Lett

  16. Effect of mental fatigue caused by mobile 3D viewing on selective attention: an ERP study.

    PubMed

    Mun, Sungchul; Kim, Eun-Soo; Park, Min-Chul

    2014-12-01

    This study investigated behavioral responses to and auditory event-related potential (ERP) correlates of mental fatigue caused by mobile three-dimensional (3D) viewing. Twenty-six participants (14 women) performed a selective attention task in which they were asked to respond to the sounds presented at the attended side while ignoring sounds at the ignored side before and after mobile 3D viewing. Considering different individual susceptibilities to 3D, participants' subjective fatigue data were used to categorize them into two groups: fatigued and unfatigued. The amplitudes of d-ERP components were defined as differences in amplitudes between time-locked brain oscillations of the attended and ignored sounds, and these values were used to calculate the degree to which spatial selective attention was impaired by 3D mental fatigue. The fatigued group showed significantly longer response times after mobile 3D viewing compared to before the viewing. However, response accuracy did not significantly change between the two conditions, implying that the participants used a behavioral strategy to cope with their performance accuracy decrement by increasing their response times. No significant differences were observed for the unfatigued group. Analysis of covariance revealed group differences with significant and trends toward significant decreases in the d-P200 and d-late positive potential (LPP) amplitudes at the occipital electrodes of the fatigued and unfatigued groups. Our findings indicate that mentally fatigued participants did not effectively block out distractors in their information processing mechanism, providing support for the hypothesis that 3D mental fatigue impairs spatial selective attention and is characterized by changes in d-P200 and d-LPP amplitudes.

  17. On an aspect of calculated molecular descriptors in QSAR studies of quinolone antibacterials.

    PubMed

    Ghosh, Payel; Thanadath, Megha; Bagchi, Manish C

    2006-08-01

    The re-emergence of tuberculosis infections, which are resistant to conventional drug therapy, has steadily risen in the last decade and as a result of that, fluoroquinolone drugs are being used as the second line of action. But there is hardly any study to examine specific structure activity relationships of quinolone antibacterials against mycobacteria. In this paper, an attempt has been made to establish a quantitative structure activity relationship modeling for a series of quinolone compounds against Mycobacterium fortuitum and Mycobacterium smegmatis. Due to lack of sufficient physicochemical data for the anti-mycobacterial compounds, it becomes very difficult to develop predictive methods based on experimental data. The present paper is an effort for the development of QSARs from the standpoint of physicochemical, constitutional, geometrical, electrostatic and topological indices. Molecular descriptors have been calculated solely from the chemical structure of N-1, C-7 and 8 substituted quinolone compounds and ridge regression models have been developed which can explain a better structure-activity relationship. Consideration of an intermolecular similarity analysis approach that led to a successful computer program development in PERL language has been used for comparing the influence of various molecular descriptors in different data subsets. The comparison of relative effectiveness of the calculated descriptors in our ridge regression model gives rise to some interesting results.

  18. QSAR study of the toxicity of nitrobenzenes to river bacteria and photobacterium phosphoreum

    SciTech Connect

    Yuan, X.; Lu, G.; Lang, P.

    1997-01-01

    Since nitrobenzenes constitute a class of industrial chemicals that are present in Songhua River and probably in many other industrialized countries as well, it is useful to gain insight into their potential hazard to aquatic organisms. For this reason, it was decided to determine data on the toxicity for bacteria in the Songhua River. Furthermore, the toxicity to Ph. phosphoreum was determined in the Microtox assay, in order to further evaluate the usefulness of this assay for hazard assessment. Quantitative structure-activity relationships (QSARs) have been developed for aromatic nitro compound toxicity to aquatic species, but no data on the toxicity of nitrobenzenes to environmental bacteria were used. In this study, the toxicity of various substituted nitrobenzenes to bacteria in Songhua River and to Ph. phosphoreum has been investigated, establishing quantitative structure-activity relationships with n-octanol-water partition coefficient (log P), the energy of the lowest unoccupied molecular orbital (E{sub LUMO}) and the sum of substituent constant ({Sigma}{sigma}-). 12 refs., 2 tabs.

  19. Supporting Distributed Team Working in 3D Virtual Worlds: A Case Study in Second Life

    ERIC Educational Resources Information Center

    Minocha, Shailey; Morse, David R.

    2010-01-01

    Purpose: The purpose of this paper is to report on a study into how a three-dimensional (3D) virtual world (Second Life) can facilitate socialisation and team working among students working on a team project at a distance. This models the situation in many commercial sectors where work is increasingly being conducted across time zones and between…

  20. Segmented images and 3D images for studying the anatomical structures in MRIs

    NASA Astrophysics Data System (ADS)

    Lee, Yong Sook; Chung, Min Suk; Cho, Jae Hyun

    2004-05-01

    For identifying the pathological findings in MRIs, the anatomical structures in MRIs should be identified in advance. For studying the anatomical structures in MRIs, an education al tool that includes the horizontal, coronal, sagittal MRIs of entire body, corresponding segmented images, 3D images, and browsing software is necessary. Such an educational tool, however, is hard to obtain. Therefore, in this research, such an educational tool which helps medical students and doctors study the anatomical structures in MRIs was made as follows. A healthy, young Korean male adult with standard body shape was selected. Six hundred thirteen horizontal MRIs of the entire body were scanned and inputted to the personal computer. Sixty anatomical structures in the horizontal MRIs were segmented to make horizontal segmented images. Coronal, sagittal MRIs and coronal, sagittal segmented images were made. 3D images of anatomical structures in the segmented images were reconstructed by surface rendering method. Browsing software of the MRIs, segmented images, and 3D images was composed. This educational tool that includes horizontal, coronal, sagittal MRIs of entire body, corresponding segmented images, 3D images, and browsing software is expected to help medical students and doctors study anatomical structures in MRIs.

  1. 3D Visualization Types in Multimedia Applications for Science Learning: A Case Study for 8th Grade Students in Greece

    ERIC Educational Resources Information Center

    Korakakis, G.; Pavlatou, E. A.; Palyvos, J. A.; Spyrellis, N.

    2009-01-01

    This research aims to determine whether the use of specific types of visualization (3D illustration, 3D animation, and interactive 3D animation) combined with narration and text, contributes to the learning process of 13- and 14- years-old students in science courses. The study was carried out with 212 8th grade students in Greece. This…

  2. 3D SEM for surface topography quantification - a case study on dental surfaces

    NASA Astrophysics Data System (ADS)

    Glon, F.; Flys, O.; Lööf, P.-J.; Rosén, B.-G.

    2014-03-01

    3D analysis of surface topography is becoming a more used tool for industry and research. New ISO standards are being launched to assist in quantifying engineering surfaces. The traditional optical measuring instrumentation used for 3D surface characterization has been optical interferometers and confocal based instrumentation. However, the resolution here is limited in the lateral dimension to the wavelength of visible light to about 500 nm. The great advantage using the SEM for topography measurements is the high flexibility to zoom from low magnifications and locating interesting areas to high magnification of down to nanometer large surface features within seconds. This paper presents surface characterization of dental implant micro topography. 3D topography data was created from SEM images using commercial photogrammetric software. A coherence scanning interferometer was used for reference measurements to compare with the 3D SEM measurements on relocated areas. As a result of this study, measurements emphasizes that the correlation between the accepted CSI measurements and the new technology represented by photogrammetry based on SEM images for many areal characterization parameters are around or less than 20%. The importance of selecting sampling and parameter sensitivity to varying sampling is high-lighted. Future work includes a broader study of limitations of the photogrammetry technique on certified micro-geometries and more application surfaces at different scales.

  3. 3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents

    NASA Astrophysics Data System (ADS)

    Andrade, Carolina Horta; Pasqualoto, Kerly F. M.; Ferreira, Elizabeth I.; Hopfinger, Anton J.

    2010-02-01

    Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt . The resulting optimized models are not only statistically significant with r 2 ranging from 0.83 to 0.92 and q 2 from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.

  4. Antibacterial Activity of Imidazolium-Based Ionic Liquids Investigated by QSAR Modeling and Experimental Studies.

    PubMed

    Hodyna, Diana; Kovalishyn, Vasyl; Rogalsky, Sergiy; Blagodatnyi, Volodymyr; Petko, Kirill; Metelytsia, Larisa

    2016-09-01

    Predictive QSAR models for the inhibitors of B. subtilis and Ps. aeruginosa among imidazolium-based ionic liquids were developed using literary data. The regression QSAR models were created through Artificial Neural Network and k-nearest neighbor procedures. The classification QSAR models were constructed using WEKA-RF (random forest) method. The predictive ability of the models was tested by fivefold cross-validation; giving q(2) = 0.77-0.92 for regression models and accuracy 83-88% for classification models. Twenty synthesized samples of 1,3-dialkylimidazolium ionic liquids with predictive value of activity level of antimicrobial potential were evaluated. For all asymmetric 1,3-dialkylimidazolium ionic liquids, only compounds containing at least one radical with alkyl chain length of 12 carbon atoms showed high antibacterial activity. However, the activity of symmetric 1,3-dialkylimidazolium salts was found to have opposite relationship with the length of aliphatic radical being maximum for compounds based on 1,3-dioctylimidazolium cation. The obtained experimental results suggested that the application of classification QSAR models is more accurate for the prediction of activity of new imidazolium-based ILs as potential antibacterials.

  5. QSAR study on the antibacterial activity of some sulfa drugs: building blockers of Mannich bases.

    PubMed

    Mandloi, Dheeraj; Joshi, Sheela; Khadikar, Padmakar V; Khosla, Navita

    2005-01-17

    Sulfa drugs are building blockers of several types of Mannich bases. Consequently, the antibacterial activities of sulfa drugs are reported in this paper, which will help in explaining and understanding antibacterial activities of Mannich bases. Reported QSAR is carried out using distance-based topological indices and discussed critically on the basis of statistical parameters.

  6. A 3D tension bioreactor platform to study the interplay between ECM stiffness and tumor phenotype.

    PubMed

    Cassereau, Luke; Miroshnikova, Yekaterina A; Ou, Guanqing; Lakins, Johnathon; Weaver, Valerie M

    2015-01-10

    Extracellular matrix (ECM) structure, composition, and stiffness have profound effects on tissue development and pathologies such as cardiovascular disease and cancer. Accordingly, a variety of synthetic hydrogel systems have been designed to study the impact of ECM composition, density, mechanics, and topography on cell and tissue phenotype. However, these synthetic systems fail to accurately recapitulate the biological properties and structure of the native tissue ECM. Natural three dimensional (3D) ECM hydrogels, such as collagen or hyaluronic acid, feature many of the chemical and physical properties of tissue, yet, these systems have limitations including the inability to independently control biophysical properties such as stiffness and pore size. Here, we present a 3D tension bioreactor system that permits precise mechanical tuning of collagen hydrogel stiffness, while maintaining consistent composition and pore size. We achieve this by mechanically loading collagen hydrogels covalently-conjugated to a polydimethylsiloxane (PDMS) membrane to induce hydrogel stiffening. We validated the biological application of this system with oncogenically transformed mammary epithelial cell organoids embedded in a 3D collagen I hydrogel, either uniformly stiffened or calibrated to create a gradient of ECM stiffening, to visually demonstrate the impact of ECM stiffening on transformation and tumor cell invasion. As such, this bioreactor presents the first tunable 3D natural hydrogel system that is capable of independently assessing the role of ECM stiffness on tissue phenotype.

  7. 3D Gravity Inversion of Northern Sinai Peninsula: A Case Study

    NASA Astrophysics Data System (ADS)

    Khalil, Mohamed A.; Santos, Fernando M.

    2014-07-01

    The Sinai Peninsula has attracted the attention of many geological and geophysical studies as it is influenced and bounded by major tectonic events. Those are (1) the Mesozoic to Early Cenozoic tectonically active opening of the Tethys, (2) the Late Cretaceous to Early Tertiary (Laramide) Syrian arc system, due to closing of the Tethys (3) the Oligo-Miocene Gulf of Suez rifted basin, and (4) the Late Miocene to Recent transform Dead Sea-Gulf of Aqaba rift. Additionally, the shear zones inside Sinai such as the Ragabet El-Naam and Minsherah-Abu Kandu Shear Zones. Each of these major tectonic events has affected dramatically the structure evolution of the northern Sinai area. The present paper estimates the 3D density contrast model using the gravity data of northern Sinai. The estimated 3D density contrast model elucidated the peculiarities of the main structural elements in the region. The estimated 3D density contrast model showed the high and low gravity anomalies that form the main mountains and main valleys in northern Sinai. The estimated low density zones are in agreement with the inferred faults resulting from the first horizontal derivative. Comparing the 3D model with the tectonic history of the region and the results of the first horizontal derivative and least square separation increased the reliability of the model.

  8. Validity Study of Vertebral Rotation Measurement Using 3-D Ultrasound in Adolescent Idiopathic Scoliosis.

    PubMed

    Wang, Qian; Li, Meng; Lou, Edmond H M; Chu, Winnie C W; Lam, Tsz-Ping; Cheng, Jack C Y; Wong, Man-Sang

    2016-07-01

    This study aimed to assess the validity of 3-D ultrasound measurements on the vertebral rotation of adolescent idiopathic scoliosis (AIS) under clinical settings. Thirty curves (mean Cobb angle: 21.7° ± 15.9°) from 16 patients with AIS were recruited. 3-D ultrasound and magnetic resonance imaging scans were performed at the supine position. Each of the two raters measured the apical vertebral rotation using the center of laminae (COL) method in the 3-D ultrasound images and the Aaro-Dahlborn method in the magnetic resonance images. The intra- and inter-reliability of the COL method was demonstrated by the intra-class correlation coefficient (ICC) (both [2, K] >0.9, p < 0.05). The COL method showed no significant difference (p < 0.05) compared with the Aaro-Dahlborn method. Furthermore, the agreement between these two methods was demonstrated by the Bland-Altman method, and high correlation was found (r > 0.9, p < 0.05). These results validated the proposed 3-D ultrasound method in the measurements of vertebral rotation in the patients with AIS.

  9. Studying Host-Pathogen Interactions In 3-D: Organotypic Models For Infectious Disease And Drug Development

    NASA Technical Reports Server (NTRS)

    Nickerson, Cheryl A.; Richter, Emily G.; Ott, C. Mark

    2006-01-01

    Representative, reproducible and high-throughput models of human cells and tissues are critical for a meaningful evaluation of host-pathogen interactions and are an essential component of the research developmental pipeline. The most informative infection models - animals, organ explants and human trials - are not suited for extensive evaluation of pathogenesis mechanisms and screening of candidate drugs. At the other extreme, more cost effective and accessible infection models such as conventional cell culture and static co-culture may not capture physiological and three-dimensional aspects of tissue biology that are important in assessing pathogenesis, and effectiveness and cytotoxicity of therapeutics. Our lab has used innovative bioengineering technology to establish biologically meaningful 3-D models of human tissues that recapitulate many aspects of the differentiated structure and function of the parental tissue in vivo, and we have applied these models to study infectious disease. We have established a variety of different 3-D models that are currently being used in infection studies - including small intestine, colon, lung, placenta, bladder, periodontal ligament, and neuronal models. Published work from our lab has shown that our 3-D models respond to infection with bacterial and viral pathogens in ways that reflect the infection process in vivo. By virtue of their physiological relevance, 3-D cell cultures may also hold significant potential as models to provide insight into the neuropathogenesis of HIV infection. Furthermore, the experimental flexibility, reproducibility, cost-efficiency, and high throughput platform afforded by these 3-D models may have important implications for the design and development of drugs with which to effectively treat neurological complications of HIV infection.

  10. 3D Echo Pilot Study of Geometric Left Ventricular Changes after Acute Myocardial Infarction

    PubMed Central

    Vieira, Marcelo Luiz Campos; Oliveira, Wercules Antonio; Cordovil, Adriana; Rodrigues, Ana Clara Tude; Mônaco, Cláudia Gianini; Afonso, Tânia; Lira Filho, Edgar Bezerra; Perin, Marco; Fischer, Cláudio Henrique; Morhy, Samira Saady

    2013-01-01

    Background Left ventricular remodeling (LVR) after AMI characterizes a factor of poor prognosis. There is little information in the literature on the LVR analyzed with three-dimensional echocardiography (3D ECHO). Objective To analyze, with 3D ECHO, the geometric and volumetric modifications of the left ventricle (VE) six months after AMI in patients subjected to percutaneous primary treatment. Methods Prospective study with 3D ECHO of 21 subjects (16 men, 56 ± 12 years-old), affected by AMI with ST segment elevation. The morphological and functional analysis (LV) with 3D ECHO (volumes, LVEF, 3D sphericity index) was carried out up to seven days and six months after the AMI. The LVR was considered for increase > 15% of the end diastolic volume of the LV (LVEDV) six months after the AMI, compared to the LVEDV up to seven days from the event. Results Eight (38%) patients have presented LVR. Echocardiographic measurements (n = 21 patients): I- up to seven days after the AMI: 1- LVEDV: 92.3 ± 22.3 mL; 2- LVEF: 0.51 ± 0.01; 3- sphericity index: 0.38 ± 0.05; II- after six months: 1- LVEDV: 107.3 ± 26.8 mL; 2- LVEF: 0.59 ± 0.01; 3- sphericity index: 0.31 ± 0.05. Correlation coefficient (r) between the sphericity index up to seven days after the AMI and the LVEDV at six months (n = 8) after the AMI: r: 0.74, p = 0.0007; (r) between the sphericity index six months after the AMI and the LVEDV at six months after the AMI: r: 0.85, p < 0.0001. Conclusion In this series, LVR has been observed in 38% of the patients six months after the AMI. The three-dimensional sphericity index has been associated to the occurrence of LVR. PMID:23740401

  11. 3D printed polyurethane prosthesis for partial tracheal reconstruction: a pilot animal study.

    PubMed

    Jung, Soo Yeon; Lee, Sang Jin; Kim, Ha Yeong; Park, Hae Sang; Wang, Zhan; Kim, Hyun Jun; Yoo, James J; Chung, Sung Min; Kim, Han Su

    2016-10-27

    A ready-made, acellular patch-type prosthesis is desirable in repairing partial tracheal defects in the clinical setting. However, many of these prostheses may not show proper biological integration and biomechanical function when they are transplanted. In this study, we developed a novel 3D printed polyurethane (PU) tracheal scaffold with micro-scale architecture to allow host tissue infiltration and adequate biomechanical properties to withstand physiological tracheal condition. A half-pipe shaped PU scaffold (1.8 cm of height, 0.18 cm thickness, and 2 cm of diameter) was fabricated by 3D printing of PU 200 μm PU beam. The 3D printed tracheal scaffolds consisted of a porous inner microstructure with 200 × 200 × 200 μm(3) sized pores and a non-porous outer layer. The mechanical properties of the scaffolds were 3.21 ± 1.02 MPa of ultimate tensile strength, 2.81 ± 0.58 MPa of Young's modulus, and 725% ± 41% of elongation at break. To examine the function of the 3D printed tracheal scaffolds in vivo, the scaffolds were implanted into 1.0 × 0.7 cm(2) sized anterior tracheal defect of rabbits. After implantation, bronchoscopic examinations revealed that the implanted tracheal scaffolds were patent for a 16 week-period. Histologic findings showed that re-epithelialization after 4 weeks of implantation and ciliated respiratory epithelium with ciliary beating after 8 weeks of implantation were observed at the lumen of the implanted tracheal scaffolds. The ingrowth of the connective tissue into the scaffolds was observed at 4 weeks after implantation. The biomechanical properties of the implanted tracheal scaffolds were continually maintained for 16 week-period. The results demonstrated that 3D printed tracheal scaffold could provide an alternative solution as a therapeutic treatment for partial tracheal defects.

  12. Adaptive clutter rejection for 3D color Doppler imaging: preliminary clinical study.

    PubMed

    Yoo, Yang Mo; Sikdar, Siddhartha; Karadayi, Kerem; Kolokythas, Orpheus; Kim, Yongmin

    2008-08-01

    In three-dimensional (3D) ultrasound color Doppler imaging (CDI), effective rejection of flash artifacts caused by tissue motion (clutter) is important for improving sensitivity in visualizing blood flow in vessels. Since clutter characteristics can vary significantly during volume acquisition, a clutter rejection technique that can adapt to the underlying clutter conditions is desirable for 3D CDI. We have previously developed an adaptive clutter rejection (ACR) method, in which an optimum filter is dynamically selected from a set of predesigned clutter filters based on the measured clutter characteristics. In this article, we evaluated the ACR method with 3D in vivo data acquired from 37 kidney transplant patients clinically indicated for a duplex ultrasound examination. We compared ACR against a conventional clutter rejection method, down-mixing (DM), using a commonly-used flow signal-to-clutter ratio (SCR) and a new metric called fractional residual clutter area (FRCA). The ACR method was more effective in removing the flash artifacts while providing higher sensitivity in detecting blood flow in the arcuate arteries and veins in the parenchyma of transplanted kidneys. ACR provided 3.4 dB improvement in SCR over the DM method (11.4 +/- 1.6 dB versus 8.0 +/- 2.0 dB, p < 0.001) and had lower average FRCA values compared with the DM method (0.006 +/- 0.003 versus 0.036 +/- 0.022, p < 0.001) for all study subjects. These results indicate that the new ACR method is useful for removing nonstationary tissue motion while improving the image quality for visualizing 3D vascular structure in 3D CDI.

  13. D Recording for 2d Delivering - the Employment of 3d Models for Studies and Analyses -

    NASA Astrophysics Data System (ADS)

    Rizzi, A.; Baratti, G.; Jiménez, B.; Girardi, S.; Remondino, F.

    2011-09-01

    In the last years, thanks to the advances of surveying sensors and techniques, many heritage sites could be accurately replicated in digital form with very detailed and impressive results. The actual limits are mainly related to hardware capabilities, computation time and low performance of personal computer. Often, the produced models are not visible on a normal computer and the only solution to easily visualized them is offline using rendered videos. This kind of 3D representations is useful for digital conservation, divulgation purposes or virtual tourism where people can visit places otherwise closed for preservation or security reasons. But many more potentialities and possible applications are available using a 3D model. The problem is the ability to handle 3D data as without adequate knowledge this information is reduced to standard 2D data. This article presents some surveying and 3D modeling experiences within the APSAT project ("Ambiente e Paesaggi dei Siti d'Altura Trentini", i.e. Environment and Landscapes of Upland Sites in Trentino). APSAT is a multidisciplinary project funded by the Autonomous Province of Trento (Italy) with the aim documenting, surveying, studying, analysing and preserving mountainous and hill-top heritage sites located in the region. The project focuses on theoretical, methodological and technological aspects of the archaeological investigation of mountain landscape, considered as the product of sequences of settlements, parcelling-outs, communication networks, resources, and symbolic places. The mountain environment preserves better than others the traces of hunting and gathering, breeding, agricultural, metallurgical, symbolic activities characterised by different lengths and environmental impacts, from Prehistory to the Modern Period. Therefore the correct surveying and documentation of this heritage sites and material is very important. Within the project, the 3DOM unit of FBK is delivering all the surveying and 3D material to

  14. 3D Propagation and Geoacoustic Inversion Studies in the Mid-Atlantic Bight

    DTIC Science & Technology

    2016-06-07

    3D Propagation and Geoacoustic Inversion Studies in the Mid-Atlantic Bight Kevin B. Smith Code PH/Sk, Department of Physics Naval Postgraduate...properties and measured transmission loss. Results from this analysis will be considered in the context of geoacoustic inversions . OBJECTIVES To...bathymetric features and ocean fronts near the shelf break of the mid-Atlantic Bight, and use of various data for geoacoutic inversion studies. The results

  15. Synthesis, antifungal activity, and QSAR studies of 1,6-dihydropyrimidine derivatives

    PubMed Central

    Rami, Chirag; Patel, Laxmanbhai; Patel, Chhaganbhai N.; Parmar, Jayshree P.

    2013-01-01

    Introduction: A practical synthesis of pyrimidinone would be very helpful for chemists because pyrimidinone is found in many bioactive natural products and exhibits a wide range of biological properties. The biological significance of pyrimidine derivatives has led us to the synthesis of substituted pyrimidine. Materials and Methods: With the aim of developing potential antimicrobials, new series of 5-cyano-6-oxo-1,6-dihydro-pyrimidine derivatives namely 2-(5-cyano-6-oxo-4-substituted (aryl)-1,6-dihydropyrimidin-2-ylthio)-N-substituted (phenyl) acetamide (C1-C41) were synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), mass analysis, and proton nuclear magnetic resonance (1H NMR). All the compounds were screened for their antifungal activity against Candida albicans (MTCC, 227). Results and Discussion: Quantitative structure activity relationship (QSAR) studies of a series of 1,6-dihydro-pyrimidine were carried out to study various structural requirements for fungal inhibition. Various lipophilic, electronic, geometric, and spatial descriptors were correlated with antifungal activity using genetic function approximation. Developed models were found predictive as indicated by their square of predictive regression values (r2pred) and their internal and external cross-validation. Study reveals that CHI_3_C, Molecular_SurfaceArea, and Jurs_DPSA_1 contributed significantly to the activity along with some electronic, geometric, and quantum mechanical descriptors. Conclusion: A careful analysis of the antifungal activity data of synthesized compounds revealed that electron withdrawing substitution on N-phenyl acetamide ring of 1,6-dihydropyrimidine moiety possess good activity. PMID:24302836

  16. QSAR Modeling is not "Push a Button and Find a Correlation": A Case Study of Toxicity of (Benzo-)triazoles on Algae.

    PubMed

    Gramatica, Paola; Cassani, Stefano; Roy, Partha Pratim; Kovarich, Simona; Yap, Chun Wei; Papa, Ester

    2012-12-01

    A case study of toxicity of (benzo)triazoles ((B)TAZs) to the algae Pseudokirchneriella subcapitata is used to discuss some problems and solutions in QSAR modeling, particularly in the environmental context. The relevance of data curation (not only of experimental data, but also of chemical structures and input formats for the calculation of molecular descriptors), the crucial points of QSAR model validation and the potential application for new chemicals (internal robustness, exclusion of chance correlation, external predictivity, applicability domain) are described, while developing MLR-OLS models based on molecular descriptors, calculated by various QSAR software tools (commercial DRAGON, free PaDEL-Descriptor and QSPR-THESAURUS). Additionally, the utility of consensus models is highlighted. This work summarizes a methodology for a rigorous statistical approach to obtain reliable QSAR predictions, also for a large number of (B)TAZs in the ECHA preregistration list of REACH (even if starting from limited experimental data availability), and has evidenced some ambiguities and discrepancies related to SMILES notations from different databases; furthermore it highlighted some general problems related to QSAR model generation and was useful in the implementation of the PaDEL-Descriptor software.

  17. Reconstruction of quadratic curves in 3D using two or more perspective views: simulation studies

    NASA Astrophysics Data System (ADS)

    Kumar, Sanjeev; Sukavanam, N.; Balasubramanian, R.

    2006-01-01

    The shapes of many natural and man-made objects have planar and curvilinear surfaces. The images of such curves usually do not have sufficient distinctive features to apply conventional feature-based reconstruction algorithms. In this paper, we describe a method of reconstruction of a quadratic curve in 3-D space as an intersection of two cones containing the respective projected curve images. The correspondence between this pair of projections of the curve is assumed to be established in this work. Using least-square curve fitting, the parameters of a curve in 2-D space are found. From this we are reconstructing the 3-D quadratic curve. Relevant mathematical formulations and analytical solutions for obtaining the equation of reconstructed curve are given. The result of the described reconstruction methodology are studied by simulation studies. This reconstruction methodology is applicable to LBW decision in cricket, path of the missile, Robotic Vision, path lanning etc.

  18. In vitro systems to study nephropharmacology: 2D versus 3D models.

    PubMed

    Sánchez-Romero, Natalia; Schophuizen, Carolien M S; Giménez, Ignacio; Masereeuw, Rosalinde

    2016-11-05

    The conventional 2-dimensional (2D) cell culture is an invaluable tool in, amongst others, cell biology and experimental pharmacology. However, cells cultured in 2D, on the top of stiff plastic plates lose their phenotypical characteristics and fail in recreating the physiological environment found in vivo. This is a fundamental requirement when the goal of the study is to get a rigorous predictive response of human drug action and safety. Recent approaches in the field of renal cell biology are focused on the generation of 3D cell culture models due to the more bona fide features that they exhibit and the fact that they are more closely related to the observed physiological conditions, and better predict in vivo drug handling. In this review, we describe the currently available 3D in vitro models of the kidney, and some future directions for studying renal drug handling, disease modeling and kidney regeneration.

  19. QSAR, docking, dynamic simulation and quantum mechanics studies to explore the recognition properties of cholinesterase binding sites.

    PubMed

    Correa-Basurto, J; Bello, M; Rosales-Hernández, M C; Hernández-Rodríguez, M; Nicolás-Vázquez, I; Rojo-Domínguez, A; Trujillo-Ferrara, J G; Miranda, René; Flores-Sandoval, C A

    2014-02-25

    A set of 84 known N-aryl-monosubstituted derivatives (42 amides: series 1 and 2, and 42 imides: series 3 an 4, from maleic and succinic anhydrides, respectively) that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesterase (ChEs) was considered for Quantitative structure-activity relationship (QSAR) studies. These QSAR studies employed docking data from both ChEs that were previously submitted to molecular dynamics (MD) simulations. Donepezil and galanthamine stereoisomers were included to analyze their quantum mechanics properties and for validating the docking procedure. Quantum parameters such as frontier orbital energies, dipole moment, molecular volume, atomic charges, bond length and reactivity parameters were measured, as well as partition coefficients, molar refractivity and polarizability were also analyzed. In order to evaluate the obtained equations, four compounds: 1a (4-oxo-4-(phenylamino)butanoic acid), 2a ((2Z)-4-oxo-4-(phenylamino)but-2-enoic acid), 3a (2-phenylcyclopentane-1,3-dione) and 4a (2-phenylcyclopent-4-ene-1,3-dione) were employed as independent data set, using only equations with r(m(test))²>0.5. It was observed that residual values gave low value in almost all series, excepting in series 1 for compounds 3a and 4a, and in series 4 for compounds 1a, 2a and 3a, giving a low value for 4a. Consequently, equations seems to be specific according to the structure of the evaluated compound, that means, series 1 fits better for compound 1a, series 3 or 4 fits better for compounds 3a or 4a. Same behavior was observed in the butyrylcholinesterase (BChE). Therefore, obtained equations in this QSAR study could be employed to calculate the inhibition constant (Ki) value for compounds having a similar structure as N-aryl derivatives described here. The QSAR study showed that bond lengths, molecular electrostatic potential and frontier orbital energies are important in both ChE targets. Docking studies revealed that

  20. Two Eyes, 3D: A New Project to Study Stereoscopy in Astronomy Education

    NASA Astrophysics Data System (ADS)

    Price, Aaron; SubbaRao, M.; Wyatt, R.

    2012-01-01

    "Two Eyes, 3D" is a 3-year NSF funded research project to study the educational impacts of using stereoscopic representations in informal settings. The project funds two experimental studies. The first is focused on how children perceive various spatial qualities of scientific objects displayed in static 2D and 3D formats. The second is focused on how adults perceive various spatial qualities of scientific objects and processes displayed in 2D and 3D movie formats. As part of the project, two brief high-definition films about variable stars will be developed. Both studies will be mixed-method and look at prior spatial ability and other demographic variables as covariates. The project is run by the American Association of Variable Star Observers, Boston Museum of Science and the Adler Planetarium and Astronomy Museum with consulting from the California Academy of Sciences. Early pilot results will be presented. All films will be released into the public domain, as will the assessment software designed to run on tablet computers (iOS or Android).

  1. A porous 3D cell culture micro device for cell migration study.

    PubMed

    Ma, Liang; Zhou, Changchun; Lin, Biaoyang; Li, Wei

    2010-08-01

    Cell migration under chemoattractant is an important biological step in cancer metastasis that causes the spread of malignant tumor cells. Porous polymeric materials are widely used to mimic the extracellular matrix (ECM) environment for applications such as three dimensional (3D) cell culturing and tissue engineering. In this paper we report a novel 3D cell culture device based on porous polymeric material to study cancer migration. We fabricated a porous channel on a polymeric chip using a selective ultrasonic foaming method. We demonstrate that a chemical concentration gradient could be established through the porous channel due to the slow diffusion process. We show that significant cell migration could be observed through the porous channel within 1-2 weeks of cell culturing when metastatic M4A4-GFP breast cancer cells were induced by 20% fetal bovine serum (FBS).We also developed a mathematical model to evaluate the diffusivity and concentration gradient through the fabricated porous structure.

  2. 3D Ultrasound Guidance of Autonomous Robotic Breast Biopsy: Feasibility Study

    PubMed Central

    Liang, Kaicheng; Rogers, Albert J.; Light, Edward D.; von Allmen, Daniel; Smith, Stephen W.

    2009-01-01

    Feasibility studies of autonomous robot biopsies in tissue have been conducted using real time 3D ultrasound combined with simple thresholding algorithms. The robot first autonomously processed 3D image volumes received from the ultrasound scanner to locate a metal rod target embedded in turkey breast tissue simulating a calcification, and in a separate experiment, the center of a water-filled void in the breast tissue simulating a cyst. In both experiments the robot then directed a needle to the desired target, with no user input required. Separate needle-touch experiments performed by the image-guided robot in a water tank yielded an rms error of 1.15 mm. PMID:19900753

  3. 3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study.

    PubMed

    Zhou, Xuan; Zhu, Wei; Nowicki, Margaret; Miao, Shida; Cui, Haitao; Holmes, Benjamin; Glazer, Robert I; Zhang, Lijie Grace

    2016-11-09

    Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technology to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithography 3D bioprinter was employed to fabricate a series of bone matrices consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocrystalline hydroxyapatite (nHA). When BrCa cells were introduced into the stromal cell-laden bioprinted matrices, we found that the growth of BrCa cells was enhanced by the presence of osteoblasts or MSCs, whereas the proliferation of the osteoblasts or MSCs was inhibited by the BrCa cells. The BrCa cells co-cultured with MSCs or osteoblasts presented increased vascular endothelial growth factor (VEGF) secretion in comparison to that of monocultured BrCa cells. Additionally, the alkaline phosphatase activity of MSCs or osteoblasts was reduced after BrCa cell co-culture. These results demonstrate that the 3D bioprinted matrix, with BrCa cells and bone stromal cells, provides a suitable model with which to study the interactive effects of cells in the context of an artificial bone microenvironment and thus may serve as a valuable tool for the investigation of postmetastatic breast cancer progression in bone.

  4. An Experimental Study of Mixing Dynamics in 3D Granular Flows

    NASA Astrophysics Data System (ADS)

    Zaman, Zafir

    Compared with the mixing of fluids, the mixing and segregation of granular materials remains one of the big questions of science. Unlike fluids, granular materials segregate based on differences in particle properties, such as density and size. For 2D granular flows, a dynamical systems framework has been effective in describing regions of mixing and segregation. However, computational and theoretical results are just starting to form a framework for 3D granular flows, such as the bi-axial spherical tumbler (BST) flow. This thesis builds on this emerging framework through a series of experimental studies with theoretical and model support with the goal of better understanding 3D mixing. The first study tests the commonly used assumption in continuum models of granular flow that single axis tumbler flow is two dimensional. Utilizing both surface and destructive subsurface imaging, this study shows that weak 3D deviations occur in the form of an axial drift within single axis tumbler flow of varying material spanwise depth. Afterward, this thesis focuses on the development of a custom-built X-ray imaging system to non-destructively visualize the tumbler subsurface. The second study revisits the axial drift and demonstrates that wall roughness impacts the curvature and overall displacement of particle trajectories throughout the tumbler domain using subsurface particle trajectories provided by the X-ray imaging system. Finally, mixing in the fully 3D BST flow is studied. In particular, 3D persistent mixing barriers that are predicted by the dynamical systems framework are shown to exist. Some barriers are remarkably persistent for as much as 500 protocol iterations despite the presence of collisional diffusion. The structures arise from two competing effects, the cutting and shuffling action of the protocol and the stretching from the flowing layer. The tumbling protocol controls the mixing behavior as well as the types of non-mixing barriers observed. Supplementary

  5. Intracranial Catheter for Integrated 3D Ultrasound Imaging & Hyperthermia: Feasibility Study

    NASA Astrophysics Data System (ADS)

    Herickhoff, Carl D.; Light, Edward D.; Bing, Kristin Frinkley; Mukundan, Srinivasan; Grant, Gerald A.; Wolf, Patrick D.; Dixon-Tulloch, Ellen; Shih, Timothy; Hsu, Stephen J.; Smith, Stephen W.

    2009-04-01

    In this study, we investigated the feasibility of an intracranial catheter transducer capable of real-time 3D (RT3D) imaging and ultrasound hyperthermia, for application in the visualization and treatment of tumors in the brain. We designed and constructed a 12 Fr, integrated matrix and linear array catheter transducer prototype for combined RT3D imaging and heating capability. This dual-mode catheter incorporated 153 matrix array elements and 11 linear array elements, on a 0.2 mm pitch, with a total aperture size of 8.4 mm×2.3 mm. This array achieved a 3.5° C in vitro temperature rise at a 2 cm focal distance in tissue-mimicking material. The dual-mode catheter prototype was compared with a Siemens 10 Fr AcuNav™ catheter as a gold standard in experiments assessing image quality and therapeutic potential, and both probes were used in a canine brain model to image anatomical structures and color Doppler blood flow and to attempt in vivo heating.

  6. Quantification of blood perfusion using 3D power Doppler: an in-vitro flow phantom study

    NASA Astrophysics Data System (ADS)

    Raine-Fenning, N. J.; Ramnarine, K. V.; Nordin, N. M.; Campbell, B. K.

    2004-01-01

    Three-dimensional (3D) power Doppler data is increasingly used to assess and quantify blood flow and tissue perfusion. The objective of this study was to assess the validity of common 3D power Doppler ‘vascularity’ indices by quantification in well characterised in-vitro flow models. A computer driven gear pump was used to circulate a steady flow of a blood mimicking fluid through various well characterised flow phantoms to investigate the effect of the number of flow channels, flow rate, depth dependent tissue attenuation, blood mimic scatter particle concentration and ultrasound settings. 3D Power Doppler data were acquired with a Voluson 530D scanner and 7.5 MHz transvaginal transducer (GE Kretz). Virtual Organ Computer-aided Analysis software (VOCAL) was used to quantify the vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). The vascular indices were affected by many factors, some intuitive and some with more complex or unexpected relationships (e.g. VI increased linearly with an increase in flow rate, blood mimic scatter particle concentration and number of flow channels, and had a complex dependence on pulse repetition frequency). Use of standardised settings and appropriate calibration are required in any attempt at relating ‘vascularity indices’ with flow.

  7. QSAR Modeling Using Large-Scale Databases: Case Study for HIV-1 Reverse Transcriptase Inhibitors.

    PubMed

    Tarasova, Olga A; Urusova, Aleksandra F; Filimonov, Dmitry A; Nicklaus, Marc C; Zakharov, Alexey V; Poroikov, Vladimir V

    2015-07-27

    Large-scale databases are important sources of training sets for various QSAR modeling approaches. Generally, these databases contain information extracted from different sources. This variety of sources can produce inconsistency in the data, defined as sometimes widely diverging activity results for the same compound against the same target. Because such inconsistency can reduce the accuracy of predictive models built from these data, we are addressing the question of how best to use data from publicly and commercially accessible databases to create accurate and predictive QSAR models. We investigate the suitability of commercially and publicly available databases to QSAR modeling of antiviral activity (HIV-1 reverse transcriptase (RT) inhibition). We present several methods for the creation of modeling (i.e., training and test) sets from two, either commercially or freely available, databases: Thomson Reuters Integrity and ChEMBL. We found that the typical predictivities of QSAR models obtained using these different modeling set compilation methods differ significantly from each other. The best results were obtained using training sets compiled for compounds tested using only one method and material (i.e., a specific type of biological assay). Compound sets aggregated by target only typically yielded poorly predictive models. We discuss the possibility of "mix-and-matching" assay data across aggregating databases such as ChEMBL and Integrity and their current severe limitations for this purpose. One of them is the general lack of complete and semantic/computer-parsable descriptions of assay methodology carried by these databases that would allow one to determine mix-and-matchability of result sets at the assay level.

  8. An in vitro 3D model using collagen coated gelatin nanofibers for studying breast cancer metastasis.

    PubMed

    Janani, G; Pillai, Mamatha M; Selvakumar, R; Bhattacharyya, Amitava; Sabarinath, C

    2017-02-07

    The study of breast cancer metastasis is limited due to poor knowledge of molecular progression of breast tumor and varied heterogeneity. For a better understanding of tumor metastasis, a reliable 3D in vitro model bridging the gap between 2D cultures and in vivo animal model studies is essential. Our study is focused on two key points: (i) designing a 3D microenvironment for studying metastasis and (ii) simulating the metastasis milieu by inducing epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET). An electrospun gelatin nanofiber matrix (EGNF) was fabricated using electrospinning and further dip coated with different concentrations of collagen to obtain surface complexity and mechanical properties, similar to connective tissues. Nanofiber matrices were physically characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and field-emission scanning electron microscopy (FESEM). The FTIR, AFM, and FESEM results indicated the crosslinking and confirmed the presence of pores in the nanofiber matrices. Comparative studies on biocompatibility, cell attachment, and the proliferation of MCF-7 cells on EGNF and collagen coated gelatin nanofibrous matrix (CCGM) revealed higher cellular attachment and proliferation in CCGM. CCGM with human metastatic breast cancer cell line (MCF-7) was taken to study breast cancer metastasis using estrogen (induces EMT) and progesterone (induces MET) hormones for 24 h. Quantitative real-time PCR was used for quantifying the expression of metastasis related genes, and fluorescence microscopy for verifying the invasion of cells to the matrices. The expression of E-cadherin and matrix metalloproteinase 2 (MMP 2) confirmed the occurrence of EMT and MET. Live cell imaging and cellular attachment showed significant increase of cellular invasion in crosslinked 0.15% CCGM that serves as a suitable non-toxic, biocompatible, and affordable scaffold for studying breast cancer

  9. A 3-D Computational Study of a Variable Camber Continuous Trailing Edge Flap (VCCTEF) Spanwise Segment

    NASA Technical Reports Server (NTRS)

    Kaul, Upender K.; Nguyen, Nhan T.

    2015-01-01

    Results of a computational study carried out to explore the effects of various elastomer configurations joining spanwise contiguous Variable Camber Continuous Trailing Edge Flap (VCCTEF) segments are reported here. This research is carried out as a proof-of-concept study that will seek to push the flight envelope in cruise with drag optimization as the objective. The cruise conditions can be well off design such as caused by environmental conditions, maneuvering, etc. To handle these off-design conditions, flap deflection is used so when the flap is deflected in a given direction, the aircraft angle of attack changes accordingly to maintain a given lift. The angle of attack is also a design parameter along with the flap deflection. In a previous 2D study,1 the effect of camber was investigated and the results revealed some insight into the relative merit of various camber settings of the VCCTEF. The present state of the art has not advanced sufficiently to do a full 3-D viscous analysis of the whole NASA Generic Transport Model (GTM) wing with VCCTEF deployed with elastomers. Therefore, this study seeks to explore the local effects of three contiguous flap segments on lift and drag of a model devised here to determine possible trades among various flap deflections to achieve desired lift and drag results. Although this approach is an approximation, it provides new insights into the "local" effects of the relative deflections of the contiguous spanwise flap systems and various elastomer segment configurations. The present study is a natural extension of the 2-D study to assess these local 3-D effects. Design cruise condition at 36,000 feet at free stream Mach number of 0.797 and a mean aerodynamic chord (MAC) based Reynolds number of 30.734x10(exp 6) is simulated for an angle of attack (AoA) range of 0 to 6 deg. In the previous 2-D study, the calculations revealed that the parabolic arc camber (1x2x3) and circular arc camber (VCCTEF222) offered the best L

  10. Monte Carlo generators for studies of the 3D structure of the nucleon

    DOE PAGES

    Avakian, Harut; D'Alesio, U.; Murgia, F.

    2015-01-23

    In this study, extraction of transverse momentum and space distributions of partons from measurements of spin and azimuthal asymmetries requires development of a self consistent analysis framework, accounting for evolution effects, and allowing control of systematic uncertainties due to variations of input parameters and models. Development of realistic Monte-Carlo generators, accounting for TMD evolution effects, spin-orbit and quark-gluon correlations will be crucial for future studies of quark-gluon dynamics in general and 3D structure of the nucleon in particular.

  11. 2D and 3D Terahertz Imaging and X-Rays CT for Sigillography Study

    NASA Astrophysics Data System (ADS)

    Fabre, M.; Durand, R.; Bassel, L.; Recur, B.; Balacey, H.; Bou Sleiman, J.; Perraud, J.-B.; Mounaix, P.

    2017-04-01

    Seals are part of our cultural heritage but the study of these objects is limited because of their fragility. Terahertz and X-Ray imaging are used to analyze a collection of wax seals from the fourteenth to eighteenth centuries. In this work, both techniques are compared in order to discuss their advantages and limits and their complementarity for conservation state study of the samples. Thanks to 3D analysis and reconstructions, defects and fractures are detected with an estimation of their depth position. The path from the parchment tongue inside the seals is also detected.

  12. 2D and 3D Terahertz Imaging and X-Rays CT for Sigillography Study

    NASA Astrophysics Data System (ADS)

    Fabre, M.; Durand, R.; Bassel, L.; Recur, B.; Balacey, H.; Bou Sleiman, J.; Perraud, J.-B.; Mounaix, P.

    2017-01-01

    Seals are part of our cultural heritage but the study of these objects is limited because of their fragility. Terahertz and X-Ray imaging are used to analyze a collection of wax seals from the fourteenth to eighteenth centuries. In this work, both techniques are compared in order to discuss their advantages and limits and their complementarity for conservation state study of the samples. Thanks to 3D analysis and reconstructions, defects and fractures are detected with an estimation of their depth position. The path from the parchment tongue inside the seals is also detected.

  13. (Q)SAR tools for priority setting: A case study with printed paper and board food contact material substances.

    PubMed

    Van Bossuyt, Melissa; Van Hoeck, Els; Raitano, Giuseppa; Manganelli, Serena; Braeken, Els; Ates, Gamze; Vanhaecke, Tamara; Van Miert, Sabine; Benfenati, Emilio; Mertens, Birgit; Rogiers, Vera

    2017-04-01

    Over the last years, more stringent safety requirements for an increasing number of chemicals across many regulatory fields (e.g. industrial chemicals, pharmaceuticals, food, cosmetics, …) have triggered the need for an efficient screening strategy to prioritize the substances of highest concern. In this context, alternative methods such as in silico (i.e. computational) techniques gain more and more importance. In the current study, a new prioritization strategy for identifying potentially mutagenic substances was developed based on the combination of multiple (quantitative) structure-activity relationship ((Q)SAR) tools. Non-evaluated substances used in printed paper and board food contact materials (FCM) were selected for a case study. By applying our strategy, 106 out of the 1723 substances were assigned 'high priority' as they were predicted mutagenic by 4 different (Q)SAR models. Information provided within the models allowed to identify 53 substances for which Ames mutagenicity prediction already has in vitro Ames test results. For further prioritization, additional support could be obtained by applying local i.e. specific models, as demonstrated here for aromatic azo compounds, typically found in printed paper and board FCM. The strategy developed here can easily be applied to other groups of chemicals facing the same need for priority ranking.

  14. Comparison of User Performance with Interactive and Static 3d Visualization - Pilot Study

    NASA Astrophysics Data System (ADS)

    Herman, L.; Stachoň, Z.

    2016-06-01

    Interactive 3D visualizations of spatial data are currently available and popular through various applications such as Google Earth, ArcScene, etc. Several scientific studies have focused on user performance with 3D visualization, but static perspective views are used as stimuli in most of the studies. The main objective of this paper is to try to identify potential differences in user performance with static perspective views and interactive visualizations. This research is an exploratory study. An experiment was designed as a between-subject study and a customized testing tool based on open web technologies was used for the experiment. The testing set consists of an initial questionnaire, a training task and four experimental tasks. Selection of the highest point and determination of visibility from the top of a mountain were used as the experimental tasks. Speed and accuracy of each task performance of participants were recorded. The movement and actions in the virtual environment were also recorded within the interactive variant. The results show that participants deal with the tasks faster when using static visualization. The average error rate was also higher in the static variant. The findings from this pilot study will be used for further testing, especially for formulating of hypotheses and designing of subsequent experiments.

  15. Automated 3D ultrasound elastography of the breast: a phantom validation study

    NASA Astrophysics Data System (ADS)

    Hendriks, Gijs A. G. M.; Holländer, Branislav; Menssen, Jan; Milkowski, Andy; Hansen, Hendrik H. G.; de Korte, Chris L.

    2016-04-01

    In breast cancer screening, the automated breast volume scanner (ABVS) was introduced as an alternative for mammography since the latter technique is less suitable for women with dense breasts. Although clinical studies show promising results, clinicians report two disadvantages: long acquisition times (>90 s) introducing breathing artefacts, and high recall rates due to detection of many small lesions of uncertain malignant potential. Technical improvements for faster image acquisition and better discrimination between benign and malignant lesions are thus required. Therefore, the aim of this study was to investigate if 3D ultrasound elastography using plane-wave imaging is feasible. Strain images of a breast elastography phantom were acquired by an ABVS-mimicking device that allowed axial and elevational movement of the attached transducer. Pre- and post-deformation volumes were acquired with different constant speeds (between 1.25 and 40.0 mm s-1) and by three protocols: Go-Go (pre- and post-volumes with identical start and end positions), Go-Return (similar to Go-Go with opposite scanning directions) and Control (pre- and post-volumes acquired per position, this protocol can be seen as reference). Afterwards, 2D and 3D cross-correlation and strain algorithms were applied to the acquired volumes and the results were compared. The Go-Go protocol was shown to be superior with better strain image quality (CNRe and SNRe) than Go-Return and to be similar as Control. This can be attributed to applying opposite mechanical forces to the phantom during the Go-Return protocol, leading to out-of-plane motion. This motion was partly compensated by using 3D cross-correlation. However, the quality was still inferior to Go-Go. Since these results were obtained in a phantom study with controlled deformations, the effect of possible uncontrolled in vivo tissue motion artefacts has to be addressed in future studies. In conclusion, it seems feasible to implement 3D ultrasound

  16. A Study of the dimensional accuracy obtained by low cost 3D printing for possible application in medicine

    NASA Astrophysics Data System (ADS)

    Kitsakis, K.; Alabey, P.; Kechagias, J.; Vaxevanidis, N.

    2016-11-01

    Low cost 3D printing' is a terminology that referred to the fused filament fabrication (FFF) technique, which constructs physical prototypes, by depositing material layer by layer using a thermal nozzle head. Nowadays, 3D printing is widely used in medical applications such as tissue engineering as well as supporting tool in diagnosis and treatment in Neurosurgery, Orthopedic and Dental-Cranio-Maxillo-Facial surgery. 3D CAD medical models are usually obtained by MRI or CT scans and then are sent to a 3D printer for physical model creation. The present paper is focused on a brief overview of benefits and limitations of 3D printing applications in the field of medicine as well as on a dimensional accuracy study of low-cost 3D printing technique.

  17. Does the mitral annulus shrink or enlarge during systole? A real-time 3D echocardiography study.

    PubMed

    Kwan, Jun; Jeon, Min-Jae; Kim, Dae-Hyeok; Park, Keum-Soo; Lee, Woo-Hyung

    2009-04-01

    This study was conducted to explore the geometrical changes of the mitral annulus during systole. The 3D shape of the mitral annulus was reconstructed in 13 normal subjects who had normal structure of the mitral apparatus using real-time 3D echocardiography (RT3DE) and 3D computer software. The two orthogonal (antero-posterior and commissure-commissure) dimensions, the areas (2D projected and 3D surface) and the non-planarity of the mitral annulus were estimated during early, mid and late systole. We demonstrated that the MA had a "saddle shape" appearance and it consistently enlarged mainly in the antero-posterior direction from early to late systole with lessening of its non-planarity, as was determined by 3D reconstruction using RT3DE and 3D computer software.

  18. 3D elastic full waveform inversion: case study from a land seismic survey

    NASA Astrophysics Data System (ADS)

    Kormann, Jean; Marti, David; Rodriguez, Juan-Esteban; Marzan, Ignacio; Ferrer, Miguel; Gutierrez, Natalia; Farres, Albert; Hanzich, Mauricio; de la Puente, Josep; Carbonell, Ramon

    2016-04-01

    Full Waveform Inversion (FWI) is one of the most advanced processing methods that is recently reaching a mature state after years of solving theoretical and technical issues such as the non-uniqueness of the solution and harnessing the huge computational power required by realistic scenarios. BSIT (Barcelona Subsurface Imaging Tools, www.bsc.es/bsit) includes a FWI algorithm that can tackle with very complex problems involving large datasets. We present here the application of this system to a 3D dataset acquired to constrain the shallow subsurface. This is where the wavefield is the most complicated, because most of the wavefield conversions takes place in the shallow region and also because the media is much more laterally heterogeneous. With this in mind, at least isotropic elastic approximation would be suitable as kernel engine for FWI. The current study explores the possibilities to apply elastic isotropic FWI using only the vertical component of the recorded seismograms. The survey covers an area of 500×500 m2, and consists in a receivers grid of 10 m×20 m combined with a 250 kg accelerated weight-drop as source on a displaced grid of 20 m×20 m. One of the main challenges in this case study is the costly 3D modeling that includes topography and substantial free surface effects. FWI is applied to a data subset (shooting lines 4 to 12), and is performed for 3 frequencies ranging from 15 to 25 Hz. The starting models are obtained from travel-time tomography and the all computation is run on 75 nodes of Mare Nostrum supercomputer during 3 days. The resulting models provide a higher resolution of the subsurface structures, and show a good correlation with the available borehole measurements. FWI allows to extend in a reliable way this 1D knowledge (borehole) to 3D.

  19. Spreading and Deposit Characteristics of a Rapid Dry Granular Avalanche Across 3D Topography: Experimental Study

    NASA Astrophysics Data System (ADS)

    Wang, Yu-Feng; Xu, Qiang; Cheng, Qian-Gong; Li, Yan; Luo, Zhong-Xu

    2016-11-01

    Aiming to understand the propagation and deposit behaviours of a granular avalanche along a 3D complex basal terrain, a new 3D experimental platform in 1/400 scale was developed according to the natural terrain of the Xiejiadianzi rock avalanche, with a series of laboratory experiments being conducted. Through the conduction of these tests, parameters, including the morphological evolution of sliding mass, run-outs and velocities of surficial particles, thickness contour and centre of final deposit, equivalent frictional coefficient, and energy dissipation, are documented and analysed, with the geomorphic control effect, material grain size effect, drop angle effect, and drop distance effect on rock avalanche mobility being discussed primarily. From the study, some interesting conclusions for a better understanding of rock avalanche along a 3D complex basal topography are reached. (1) For the granular avalanche tested in this study, great differences between the evolutions of the debris along the right and left branch valleys were observed, with an obvious geomorphic control effect on avalanche mobility presented. In addition, some other interesting features, including groove-like trough and superelevation, were also observed under the control of the topographic interferences. (2) The equivalent frictional coefficients of the granular avalanches tested here range from 0.48 to 0.57, which is lower than that reached with a set-up composed of an inclined chute and horizontal plate and higher than that reached using a set-up composed of only an inclined chute. And the higher the drop angle and fine particle content, the higher the equivalent frictional coefficient. The effect of drop distance on avalanche mobility is minor. (3) For a granular avalanche, momentum transfer plays an important role in the motion of mass, which can accelerate the mobility of the front part greatly through delivering the kinetic energy of the rear part to the front.

  20. 3D virtual human atria: A computational platform for studying clinical atrial fibrillation.

    PubMed

    Aslanidi, Oleg V; Colman, Michael A; Stott, Jonathan; Dobrzynski, Halina; Boyett, Mark R; Holden, Arun V; Zhang, Henggui

    2011-10-01

    Despite a vast amount of experimental and clinical data on the underlying ionic, cellular and tissue substrates, the mechanisms of common atrial arrhythmias (such as atrial fibrillation, AF) arising from the functional interactions at the whole atria level remain unclear. Computational modelling provides a quantitative framework for integrating such multi-scale data and understanding the arrhythmogenic behaviour that emerges from the collective spatio-temporal dynamics in all parts of the heart. In this study, we have developed a multi-scale hierarchy of biophysically detailed computational models for the human atria--the 3D virtual human atria. Primarily, diffusion tensor MRI reconstruction of the tissue geometry and fibre orientation in the human sinoatrial node (SAN) and surrounding atrial muscle was integrated into the 3D model of the whole atria dissected from the Visible Human dataset. The anatomical models were combined with the heterogeneous atrial action potential (AP) models, and used to simulate the AP conduction in the human atria under various conditions: SAN pacemaking and atrial activation in the normal rhythm, break-down of regular AP wave-fronts during rapid atrial pacing, and the genesis of multiple re-entrant wavelets characteristic of AF. Contributions of different properties of the tissue to mechanisms of the normal rhythm and arrhythmogenesis were investigated. Primarily, the simulations showed that tissue heterogeneity caused the break-down of the normal AP wave-fronts at rapid pacing rates, which initiated a pair of re-entrant spiral waves; and tissue anisotropy resulted in a further break-down of the spiral waves into multiple meandering wavelets characteristic of AF. The 3D virtual atria model itself was incorporated into the torso model to simulate the body surface ECG patterns in the normal and arrhythmic conditions. Therefore, a state-of-the-art computational platform has been developed, which can be used for studying multi

  1. Mechanisms of clay smear formation in 3D - a field study

    NASA Astrophysics Data System (ADS)

    Kettermann, Michael; Tronberens, Sebastian; Urai, Janos; Asmus, Sven

    2016-04-01

    Clay smears in sedimentary basins are important factors defining the sealing properties of faults. However, as clay smears are highly complex 3D structures, processes involved in the formation and deformation of clay smears are not well identified and understood. To enhance the prediction of sealing properties of clay smears extensive studies of these structures are necessary including the 3D information. We present extraordinary outcrop data from an open cast lignite mine (Hambach) in the Lower Rhine Embayment, Germany. The faults formed at a depth of 150 m, and have Shale Gouge Ratios between 0.1 and 0.3. Material in the fault zones is layered, with sheared sand, sheared clay and tectonically mixed sand-clay gouge. We studied the 3D thickness distribution of clay smear from a series of thin-spaced incremental cross-sections and several cross-sections in larger distances along the fault. Additionally, we excavated two large clay smear surfaces. Our observations show that clay smears are strongly affected by R- and R'-shears, mostly at the footwall side of our outcrops. These shears can locally cross and offset clay smears, forming holes. Thinnest parts of the clay smears are often located close to source layer cutoffs. Investigating the 3D thickness of the clay smears shows a heterogeneous distribution, rather than a continuous thinning of the smear with increasing distance to the source layers. We found two types of layered clay smears: one with continuous sheared sand between two clay smears providing vertical pathways for fluid flow, and one which consists of overlapping clay patches separated by sheared sand that provide a tortuous pathway across the clay smear. On smaller scale we identified grain-scale mixing as an important process for the formation of clay smears. Sand can be entrained into the clay smear by mixing from the surrounding host rock as well as due to intense shearing of sand lenses that were incorporated into the smear. This causes clay smears

  2. Image informatics for studying signal transduction in cells interacting with 3D matrices

    NASA Astrophysics Data System (ADS)

    Tzeranis, Dimitrios S.; Guo, Jin; Chen, Chengpin; Yannas, Ioannis V.; Wei, Xunbin; So, Peter T. C.

    2014-03-01

    Cells sense and respond to chemical stimuli on their environment via signal transduction pathways, complex networks of proteins whose interactions transmit chemical information. This work describes an implementation of image informatics, imaging-based methodologies for studying signal transduction networks. The methodology developed focuses on studying signal transduction networks in cells that interact with 3D matrices. It utilizes shRNA-based knock down of network components, 3D high-content imaging of cells inside the matrix by spectral multi-photon microscopy, and single-cell quantification using features that describe both cell morphology and cell-matrix adhesion pattern. The methodology is applied in a pilot study of TGFβ signaling via the SMAD pathway in fibroblasts cultured inside porous collagen-GAG scaffolds, biomaterials similar to the ones used clinically to induce skin regeneration. Preliminary results suggest that knocking down all rSMAD components affects fibroblast response to TGFβ1 and TGFβ3 isoforms in different ways, and suggest a potential role for SMAD1 and SMAD5 in regulating TGFβ isoform response. These preliminary results need to be verified with proteomic results that can provide solid evidence about the particular role of individual components of the SMAD pathway.

  3. 3-D LTCC microfluidic device as a tool for studying nanoprecipitation

    NASA Astrophysics Data System (ADS)

    Schianti, J. N.; Cerize, N. P. N.; Oliveira, A. M.; Derenzo, S.; Góngora-Rubio, M. R.

    2013-03-01

    Nanoparticles have been used to improve the properties of many cosmetic products, mainly the sunscreens materials using nanoencapsulation or nanosuspensions, improving the contact with active molecules, enhancing the sun protection effect and facilitating formulations in industrial products. Microfluidic devices offer an important possibility in producing nanoparticles in a simple way, in one step bottom up technique, continuum process with low polidispersivity, low consumption of reagents and additives. In this work, we microfabricated a 3-D LTCC microfluidic device to study the nanoprecipitation of Benzophenone-3, used as a sunscreen in pharmaceutical products. It was observed that some parameters influence the particle size related to the total fluid flow on device, the ratio between phases, and the Benzophenone-3 initial concentration. The influence of applied voltages on particle sizes was tested also. For the processing, a high voltage was applied in a Kovar tube inserted in the 3D device. The use of microfluidic device resulted in particles with 100 up to 800 nm of size, with polispersivity index below 0.3 and offering an interesting way to obtain nanoparticles. These studies are still ongoing, but early results indicate the possibility of obtaining B-3 nanostructured material.

  4. An experimental and numerical study of 3-D braided structural textile composites

    SciTech Connect

    Abusafieh, A.; Kalidindi, S.R.; Franco, E.

    1994-12-31

    It has been reported in literature that isostrain models (also known as Fabric Geometry Models) provide good predictions of the elastic moduli of three-dimensional textile composites. This study reports a critical evaluation of the accuracy of the isostrain models by comparing the predictions against experimental measurements as well as finite element simulations of representative unit cells of the 3-D braided composites, over a range of braid angles and volume fractions. The accuracy of the isostrain model is found to be highly sensitive to the braid angles and the fraction of lay-in axial fibers in the composite system. Good correlations between isostrain model predictions of elastic moduli and measurements were observed when the loading direction is oriented along one of the fiber directions and is significantly away from the other fiber systems in the unit cell. In other situations, however, the isostrain model predictions were in significant errors. This study also reports on the influence of various modeling parameters in the development of finite element models for the simulation of the 3-D textile composite unit cells.

  5. Study of 3D printing method for GRIN micro-optics devices

    NASA Astrophysics Data System (ADS)

    Wang, P. J.; Yeh, J. A.; Hsu, W. Y.; Cheng, Y. C.; Lee, W.; Wu, N. H.; Wu, C. Y.

    2016-03-01

    Conventional optical elements are based on either refractive or reflective optics theory to fulfill the design specifications via optics performance data. In refractive optical lenses, the refractive index of materials and radius of curvature of element surfaces determine the optical power and wavefront aberrations so that optical performance can be further optimized iteratively. Although gradient index (GRIN) phenomenon in optical materials is well studied for more than a half century, the optics theory in lens design via GRIN materials is still yet to be comprehensively investigated before realistic GRIN lenses are manufactured. In this paper, 3D printing method for manufacture of micro-optics devices with special features has been studied based on methods reported in the literatures. Due to the additive nature of the method, GRIN lenses in micro-optics devices seem to be readily achievable if a design methodology is available. First, derivation of ray-tracing formulae is introduced for all possible structures in GRIN lenses. Optics simulation program is employed for characterization of GRIN lenses with performance data given by aberration coefficients in Zernike polynomial. Finally, a proposed structure of 3D printing machine is described with conceptual illustration.

  6. 3D Numerical Study of the Shear Rheology of a Semi-dilute Viscoelastic Suspension

    NASA Astrophysics Data System (ADS)

    Yang, Mengfei; Krishnan, Sreenath; Shaqfeh, Eric

    2016-11-01

    The stress in suspensions of rigid particles in polymer solutions is of considerable interest in applications such as manufacturing processes and fracturing technologies. Deriving an analytic expression for the material functions of a viscoelastic suspension under shear is difficult due to the nonlinear particle-fluid and particle-particle interactions, and theoretical studies have been limited to dilute suspensions at low shear Weissenberg number (Wi) or low polymer concentrations. Previously, we performed 3D single-particle simulations and showed that the results agreed well with the existing theories in the appropriate parameter regimes. We found that suspensions in constant-viscosity elastic fluids shear-thicken over a range of Wi and their material properties plateau at higher Wi. However, discrepancies between simulation and existing experimental measurements for volume fractions as low as 2.5% suggested that interparticle hydrodynamic interactions could not be neglected. We now present 3D high fidelity numerical simulations of multiple spheres freely suspended in a sheared viscoelastic fluid using an immersed boundary framework to study the relationship between hydrodynamic interactions, particle structure formation, and the bulk rheology of viscoelastic suspensions. We observe that in a non-shear thinning elastic fluid, particles do not "chain", but their interactions induce additional polymer stresses in the fluid which contribute to a stronger particle effect than predicted in the dilute limit.

  7. The study of craniofacial growth patterns using 3D laser scanning and geometric morphometrics

    NASA Astrophysics Data System (ADS)

    Friess, Martin

    2006-02-01

    Throughout childhood, braincase and face grow at different rates and therefore exhibit variable proportions and positions relative to each other. Our understanding of the direction and magnitude of these growth patterns is crucial for many ergonomic applications and can be improved by advanced 3D morphometrics. The purpose of this study is to investigate this known growth allometry using 3D imaging techniques. The geometry of the head and face of 840 children, aged 2 to 19, was captured with a laser surface scanner and analyzed statistically. From each scan, 18 landmarks were extracted and registered using General Procrustes Analysis (GPA). GPA eliminates unwanted variation due to position, orientation and scale by applying a least-squares superimposition algorithm to individual landmark configurations. This approach provides the necessary normalization for the study of differences in size, shape, and their interaction (allometry). The results show that throughout adolescence, boys and girls follow a different growth trajectory, leading to marked differences not only in size but also in shape, most notably in relative proportions of the braincase. These differences can be observed during early childhood, but become most noticeable after the age of 13 years, when craniofacial growth in girls slows down significantly, whereas growth in boys continues for at least 3 more years.

  8. Numerical 3D Hydrodynamics Study of Gravitational Instabilities in a Circumbinary Disk

    NASA Astrophysics Data System (ADS)

    Desai, Karna Mahadev; Steiman-Cameron, Thomas Y.; Michael, Scott; Cai, Kai; Durisen, Richard H.

    2016-01-01

    We present a 3D hydrodynamical study of gravitational instabilities (GIs) in a circumbinary protoplanetary disk around a Solar mass star and a brown dwarf companion (0.02 M⊙). GIs can play an important, and at times dominant, role in driving the structural evolution of protoplanetary disks. The reported simulations were performed employing CHYMERA, a radiative 3D hydrodynamics code developed by the Indiana University Hydrodynamics Group. The simulations include disk self-gravity and radiative cooling governed by realistic dust opacities. We examine the role of GIs in modulating the thermodynamic state of the disks, and determine the strengths of GI-induced density waves, non-axisymmetric density structures, radial mass transport, and gravitational torques. The principal goal of this study is to determine how the presence of the companion affects the nature and strength of GIs. Results are compared with a parallel simulation of a protoplanetary disk without the presence of the brown dwarf binary companion. We detect no fragmentation in either disk. A persistent vortex forms in the inner region of both disks. The vortex seems to be stabilized by the presence of the binary companion.

  9. Structure-based modeling of dye-fiber affinity with SOM-4D-QSAR paradigm: application to set of anthraquinone derivatives.

    PubMed

    Bak, Andrzej; Wyszomirski, Miroslaw; Magdziarz, Tomasz; Smolinski, Adam; Polanski, Jaroslaw

    2014-01-01

    A comparative structure-affinity study of anthraquinone dyes adsorption on cellulose fibre is presented in this paper. We used receptor-dependent 4D-QSAR methods based on grid and neural (SOM) methodology coupled with IVEPLS procedure. The applied RD 4D-QSAR approach focuses mainly on the ability of mapping dye properties to verify the concept of tinctophore in dye chemistry. Moreover, the stochastic SMV procedure to investigate the predictive ability of the method for a large population of 4D-QSAR models was employed. The obtained findings were compared with the previously published RI 3D/4D-QSAR models for the corresponding anthraquinone trainings sets. The neutral (protonated) and anionic (deprotonated) forms of anthraquinone scaffold were examined in order to deal with the uncertainty of the dye ionization state. The results are comparable to both the neutral and anionic dye sets regardless of the occupancy and charge descriptors applied, respectively. It is worth noting that the SOM-4D-QSAR behaves comparably to the cubic counterpart which is observed in each training/test subset specification (4D-QSAR-Jo vs SOM- 4D-QSARo and 4D-QSAR-Jq vs SOM-4D-QSARq). Additionally, an attempt was made to specify a common set of variables contributing significantly to dye-fiber binding affinity; it was simultaneously performed for some arbitrary chosen SMV models. The presented RD 4D-QSAR methodology together with IVE-PLS procedure provides a robust and predictive modeling technique, which facilitates detailed specification of the molecular motifs significantly contributing to the fiber-dye affinity.

  10. Test Problems for Reactive Flow HE Model in the ALE3D Code and Limited Sensitivity Study

    SciTech Connect

    Gerassimenko, M.

    2000-03-01

    We document quick running test problems for a reactive flow model of HE initiation incorporated into ALE3D. A quarter percent change in projectile velocity changes the outcome from detonation to HE burn that dies down. We study the sensitivity of calculated HE behavior to several parameters of practical interest where modeling HE initiation with ALE3D.

  11. Human Microtumors Generated in 3D: Novel Tools for Integrated In Situ Studies of Cancer Immunotherapies.

    PubMed

    Hambach, Lothar; Buser, Andreas; Vermeij, Marcel; Pouw, Nadine; van der Kwast, Theo; Goulmy, Els

    2016-01-01

    Cellular immunotherapy targeting human tumor antigens is a promising strategy to treat solid tumors. Yet clinical results of cellular immunotherapy are disappointing. Moreover, the currently available in vitro human tumor models are not designed to study the optimization of T-cell therapies of solid tumors. Here, we describe a novel assay for multiparametric in situ analysis of therapeutic effects on individual human three-dimensional (3D) tumors. In this assay, tumors of several millimeter diameter are generated from human cancer cell lines of different tumor entities in a collagen type I microenvironment. A newly developed approach for efficient morphological analysis reveals that these in vitro tumors resemble many characteristics of the corresponding clinical cancers such as histological features, immunohistochemical staining patterns, distinct tumor growth compartments and heterogeneous protein expression. To assess the response to therapy with tumor antigen specific T-cells, standardized protocols are described to determine T-cell infiltration and tumor destruction by monitoring soluble factors and tumor growth. Human tumors engineered in 3D collagen scaffolds are excellent in vitro surrogates for avascular tumor stages allowing integrated analyses of the antitumor efficacy of cancer specific immunotherapy in situ.

  12. VA-086 methacrylate gelatine photopolymerizable hydrogels: A parametric study for highly biocompatible 3D cell embedding.

    PubMed

    Occhetta, Paola; Visone, Roberta; Russo, Laura; Cipolla, Laura; Moretti, Matteo; Rasponi, Marco

    2015-06-01

    The ability to replicate in vitro the native extracellular matrix (ECM) features and to control the three-dimensional (3D) cell organization plays a fundamental role in obtaining functional engineered bioconstructs. In tissue engineering (TE) applications, hydrogels have been successfully implied as biomatrices for 3D cell embedding, exhibiting high similarities to the natural ECM and holding easily tunable mechanical properties. In the present study, we characterized a promising photocrosslinking process to generate cell-laden methacrylate gelatin (GelMA) hydrogels in the presence of VA-086 photoinitiator using a ultraviolet LED source. We investigated the influence of prepolymer concentration and light irradiance on mechanical and biomimetic properties of resulting hydrogels. In details, the increasing of gelatin concentration resulted in enhanced rheological properties and shorter polymerization time. We then defined and validated a reliable photopolymerization protocol for cell embedding (1.5% VA-086, LED 2 mW/cm2) within GelMA hydrogels, which demonstrated to support bone marrow stromal cells viability when cultured up to 7 days. Moreover, we showed how different mechanical properties, derived from different crosslinking parameters, strongly influence cell behavior. In conclusion, this protocol can be considered a versatile tool to obtain biocompatible cell-laden hydrogels with properties easily adaptable for different TE applications.

  13. Numerical and experimental study of gas flows in 2D and 3D microchannels

    NASA Astrophysics Data System (ADS)

    Guo, Xiaohui; Huang, Chihyung; Alexeenko, Alina; Sullivan, John

    2008-02-01

    In the experiments conducted at Purdue, the air flow in rectangular cross-section microchannels was investigated using pressure sensitive paint. The high resolution pressure measurements were obtained for inlet-to-outlet pressure ratios from 1.76 to 20 with the outlet Knudsen numbers in the range from 0.003 to 0.4 based on the hydraulic diameter of 151.7 µm and the length-to-height ratio of about 50. In the slip flow regime, the air flow was simulated by the 2D and 3D Navier-Stokes equations with no-slip and slip boundary conditions. For various pressure ratios, the entrance flow development, compressibility and rarefaction effects were observed in both experiments and numerical simulations. It was found that the accurate modeling of gas flows in finite-length channels requires the inlet and outlet reservoirs to be included in computations. Effects of entrance geometry on the friction factor were studied for 3D cases. In both experiments and numerical modeling, significant pressure drop was found starting at the inlet chamber. The numerical modeling also predicted an apparent temperature drop at the channel exit.

  14. A biofidelic 3D culture model to study the development of brain cellular systems.

    PubMed

    Ren, M; Du, C; Herrero Acero, E; Tang-Schomer, M D; Özkucur, N

    2016-04-26

    Little is known about how cells assemble as systems during corticogenesis to generate collective functions. We built a neurobiology platform that consists of fetal rat cerebral cortical cells grown within 3D silk scaffolds (SF). Ivermectin (Ivm), a glycine receptor (GLR) agonist, was used to modulate cell resting membrane potential (Vmem) according to methods described in a previous work that implicated Ivm in the arrangement and connectivity of cortical cell assemblies. The cells developed into distinct populations of neuroglial stem/progenitor cells, mature neurons or epithelial-mesenchymal cells. Importantly, the synchronized electrical activity in the newly developed cortical assemblies could be recorded as local field potential (LFP) measurements. This study therefore describes the first example of the development of a biologically relevant cortical plate assembly outside of the body. This model provides i) a preclinical basis for engineering cerebral cortex tissue autografts and ii) a biofidelic 3D culture model for investigating biologically relevant processes during the functional development of cerebral cortical cellular systems.

  15. Reliability and validity of the tritrac-R3D accelerometer during backpacking: a case study.

    PubMed

    DeVoe, D; Dalleck, L

    2001-08-01

    This study investigated the utility of the Tritrac-R3D accelerometer as a reliable and valid instrument in the quantification of physical activity while backpacking in the field and to evaluate heart-rate responses and oxygen consumption to assess the feasibility of using the Tritrac-R3D to estimate caloric expenditure. Two 7-day backpacking expeditions were conducted in two consecutive years by a single subject at Grand Canyon National Park, Arizona. The average hiking heart rate ranged front 60% to 77% HRmax during the expeditions. The average rate of estimated caloric cost ranged from 6.8 to 11.7 kcals x min.(-1) (equivalent to 408 to 702 kcals x hr.(-1)), indicating a relatively moderate to high level of exertion. The Tritrac had adequate consistency and reliability in the field between the two expeditions in recorded activity counts. The Tritrac underestimated caloric expenditure during backpacking with changes in terrain, and hiking speed contributed to even greater disparity in accuracy.

  16. RF study and 3-D simulations of a side-coupling thermionic RF-gun

    NASA Astrophysics Data System (ADS)

    Rimjaem, S.; Kusoljariyakul, K.; Thongbai, C.

    2014-02-01

    A thermionic RF-gun for generating ultra-short electron bunches was optimized, developed and used as a source at a linac-based THz radiation research laboratory of the Plasma and Beam Physics Research Facility, Chiang Mai University, Thailand. The RF-gun is a π/2-mode standing wave structure, which consists of two S-band accelerating cells and a side-coupling cavity. The 2856 MHz RF wave is supplied from an S-band klystron to the gun through the waveguide input-port at the cylindrical wall of the second cell. A fraction of the RF power is coupled from the second cell to the first one via a side-coupling cavity. Both the waveguide input-port and the side-coupling cavity lead to an asymmetric geometry of the gun. RF properties and electromagnetic field distributions inside the RF-gun were studied and numerically simulated by using computer codes SUPERFISH 7.19 and CST Microwave Studio 2012©. RF characterizations and tunings of the RF-gun were performed to ensure the reliability of the gun operation. The results from 3D simulations and measurements are compared and discussed in this paper. The influence of asymmetric field distributions inside the RF-gun on the electron beam properties was investigated via 3D beam dynamics simulations. A change in the coupling-plane of the side-coupling cavity is suggested to improve the gun performance.

  17. Shear Behavior of 3D Woven Hollow Integrated Sandwich Composites: Experimental, Theoretical and Numerical Study

    NASA Astrophysics Data System (ADS)

    Zhou, Guangming; Liu, Chang; Cai, Deng'an; Li, Wenlong; Wang, Xiaopei

    2016-11-01

    An experimental, theoretical and numerical investigation on the shear behavior of 3D woven hollow integrated sandwich composites was presented in this paper. The microstructure of the composites was studied, then the shear modulus and load-deflection curves were obtained by double lap shear tests on the specimens in two principal directions of the sandwich panels, called warp and weft. The experimental results showed that the shear modulus of the warp was higher than that of the weft and the failure occurred in the roots of piles. A finite element model was established to predict the shear behavior of the composites. The simulated results agreed well with the experimental data. Simultaneously, a theoretical method was developed to predict the shear modulus. By comparing with the experimental data, the accuracy of the theoretical method was verified. The influence of structural parameters on shear modulus was also discussed. The higher yarn number, yarn density and dip angle of the piles could all improve the shear modulus of 3D woven hollow integrated sandwich composites at different levels, while the increasing height would decrease the shear modulus.

  18. A small animal image guided irradiation system study using 3D dosimeters

    NASA Astrophysics Data System (ADS)

    Qian, Xin; Admovics, John; Wuu, Cheng-Shie

    2015-01-01

    In a high resolution image-guided small animal irradiation platform, a cone beam computed tomography (CBCT) is integrated with an irradiation unit for precise targeting. Precise quality assurance is essential for both imaging and irradiation components. The conventional commissioning techniques with films face major challenges due to alignment uncertainty and labour intensive film preparation and scanning. In addition, due to the novel design of this platform the mouse stage rotation for CBCT imaging is perpendicular to the gantry rotation for irradiation. Because these two rotations are associated with different mechanical systems, discrepancy between rotation isocenters exists. In order to deliver x-ray precisely, it is essential to verify coincidence of the imaging and the irradiation isocenters. A 3D PRESAGE dosimeter can provide an excellent tool for checking dosimetry and verifying coincidence of irradiation and imaging coordinates in one system. Dosimetric measurements were performed to obtain beam profiles and percent depth dose (PDD). Isocentricity and coincidence of the mouse stage and gantry rotations were evaluated with starshots acquired using PRESAGE dosimeters. A single PRESAGE dosimeter can provide 3 -D information in both geometric and dosimetric uncertainty, which is crucial for translational studies.

  19. A comparative study of bio-inspired protective scales using 3D printing and mechanical testing.

    PubMed

    Martini, Roberto; Balit, Yanis; Barthelat, Francois

    2017-03-16

    Flexible natural armors from fish, alligators or armadillo are attracting an increasing amount of attention for their unique combinations of hardness, flexibility and light weight. The extreme contrast of stiffness between hard scales and surrounding soft tissues gives rise to unusual and attractive mechanisms, which now serve as models for the design of bio-inspired armors. Despite this growing interest, there is little guideline for the choice of materials, optimum thickness, size, shape and arrangement for the protective scales. In this work, we explore how the geometry and arrangement of hard scales can be tailored to promote scale-scale interactions. We use 3D printing to fabricate arrays of scales with increasingly complex geometries and arrangements, from simple squares with no overlap to complex ganoid-scales with overlaps and interlocking features. We performed puncture tests and flexural tests on each of the 3D printed materials, and we report the puncture resistance - compliance characteristics of each design on an Ashby chart. The interactions between the scales can significantly increase the resistance to puncture, and these interactions can be maximized by tuning the geometry and arrangement of the scales. Interestingly, the designs that offer the best combinations of puncture resistance and flexural compliance are similar to the geometry and arrangement of natural teleost and ganoid scales, which suggests that natural evolution has shaped these systems to maximize flexible protection. This study yields new insights into the mechanisms of natural dermal armor, and also suggests new designs for personal protective systems.

  20. Computational Study of 3-D Hot-Spot Initiation in Shocked Insensitive High-Explosive

    NASA Astrophysics Data System (ADS)

    Najjar, F. M.; Howard, W. M.; Fried, L. E.

    2011-06-01

    High explosive shock sensitivity is controlled by a combination of mechanical response, thermal properties, and chemical properties. The interplay of these physical phenomena in realistic condensed energetic materials is currently lacking. A multiscale computational framework is developed investigating hot spot (void) ignition in a single crystal of an insensitive HE, TATB. Atomistic MD simulations are performed to provide the key chemical reactions and these reaction rates are used in 3-D multiphysics simulations. The multiphysics code, ALE3D, is linked to the chemistry software, Cheetah, and a three-way coupled approach is pursued including hydrodynamics, thermal and chemical analyses. A single spherical air bubble is embedded in the insensitive HE and its collapse due to shock initiation is evolved numerically in time; while the ignition processes due chemical reactions are studied. Our current predictions showcase several interesting features regarding hot spot dynamics including the formation of a ``secondary'' jet. Results obtained with hydro-thermo-chemical processes leading to ignition growth will be discussed for various pore sizes and different shock pressures. LLNL-ABS-471438. This work performed under the auspices of the U.S. Department of Energy by LLNL under Contract DE-AC52-07NA27344.

  1. A biofidelic 3D culture model to study the development of brain cellular systems

    PubMed Central

    Ren, M.; Du, C.; Herrero Acero, E.; Tang-Schomer, M. D.; Özkucur, N.

    2016-01-01

    Little is known about how cells assemble as systems during corticogenesis to generate collective functions. We built a neurobiology platform that consists of fetal rat cerebral cortical cells grown within 3D silk scaffolds (SF). Ivermectin (Ivm), a glycine receptor (GLR) agonist, was used to modulate cell resting membrane potential (Vmem) according to methods described in a previous work that implicated Ivm in the arrangement and connectivity of cortical cell assemblies. The cells developed into distinct populations of neuroglial stem/progenitor cells, mature neurons or epithelial-mesenchymal cells. Importantly, the synchronized electrical activity in the newly developed cortical assemblies could be recorded as local field potential (LFP) measurements. This study therefore describes the first example of the development of a biologically relevant cortical plate assembly outside of the body. This model provides i) a preclinical basis for engineering cerebral cortex tissue autografts and ii) a biofidelic 3D culture model for investigating biologically relevant processes during the functional development of cerebral cortical cellular systems. PMID:27112667

  2. A 3D numerical study of antimicrobial persistence in heterogeneous multi-species biofilms.

    PubMed

    Zhao, Jia; Shen, Ya; Haapasalo, Markus; Wang, Zhejun; Wang, Qi

    2016-03-07

    We develop a 3D hydrodynamic model to investigate the mechanism of antimicrobial persistence in a multi-species oral biofilm and its recovery after being treated by bisbiguanide chlorhexidine gluconate (CHX). In addition to the hydrodynamic transport in the spatially heterogeneous biofilm, the model also includes mechanisms of solvent-biomass interaction, bacterial phenotype conversion, and bacteria-drug interaction. A numerical solver for the model is developed using a second order numerical scheme in 3D space and time and implemented on GPUs for high-performance computing. The model is calibrated against a set of experimental data obtained using confocal laser scan microscopy (CLSM) on multi-species oral biofilms, where a quantitative agreement is reached. Our numerical results reveal that quorum sensing molecules and growth factors in this model are instrumental in biofilm formation and recovery after the antimicrobial treatment. In particular, we show that (i) young biofilms are more susceptible to the antimicrobial treatment than the mature ones, (ii) this phenomenon is strongly correlated with volume fractions of the persister and EPS in the biofilm being treated. This suggests that antimicrobial treatment should be best administered to biofilms earlier before they mature to produce a thick protective EPS layer. In addition, the numerical study also indicates that an antimicrobial effect can be achieved should a proper mechanism be devised to minimize the conversion of susceptible bacteria to persisters during and even after the treatment.

  3. Liner Optimization Studies Using the Ducted Fan Noise Prediction Code TBIEM3D

    NASA Technical Reports Server (NTRS)

    Dunn, M. H.; Farassat, F.

    1998-01-01

    In this paper we demonstrate the usefulness of the ducted fan noise prediction code TBIEM3D as a liner optimization design tool. Boundary conditions on the interior duct wall allow for hard walls or a locally reacting liner with axially segmented, circumferentially uniform impedance. Two liner optimization studies are considered in which farfield noise attenuation due to the presence of a liner is maximized by adjusting the liner impedance. In the first example, the dependence of optimal liner impedance on frequency and liner length is examined. Results show that both the optimal impedance and attenuation levels are significantly influenced by liner length and frequency. In the second example, TBIEM3D is used to compare radiated sound pressure levels between optimal and non-optimal liner cases at conditions designed to simulate take-off. It is shown that significant noise reduction is achieved for most of the sound field by selecting the optimal or near optimal liner impedance. Our results also indicate that there is relatively large region of the impedance plane over which optimal or near optimal liner behavior is attainable. This is an important conclusion for the designer since there are variations in liner characteristics due to manufacturing imprecisions.

  4. Non-Newtonian Fluids Spreading with Surface Tension Effect: 3D Numerical Analysis Using FEM and Experimental Study

    NASA Astrophysics Data System (ADS)

    Hu, Bin; Kieweg, Sarah

    2010-11-01

    Gravity-driven thin film flow down an incline is studied for optimal design of polymeric drug delivery vehicles, such as anti-HIV topical microbicides. We develop a 3D FEM model using non-Newtonian mechanics to model the flow of gels in response to gravity, surface tension and shear-thinning. Constant volume setup is applied within the lubrication approximation scope. The lengthwise profiles of the 3D model agree with our previous 2D finite difference model, while the transverse contact line patterns of the 3D model are compared to the experiments. With incorporation of surface tension, capillary ridges are observed at the leading front in both 2D and 3D models. Previously published studies show that capillary ridge can amplify the fingering instabilities in transverse direction. Sensitivity studies (2D & 3D) and experiments are carried out to describe the influence of surface tension and shear-thinning on capillary ridge and fingering instabilities.

  5. Procedural 3d Modelling for Traditional Settlements. The Case Study of Central Zagori

    NASA Astrophysics Data System (ADS)

    Kitsakis, D.; Tsiliakou, E.; Labropoulos, T.; Dimopoulou, E.

    2017-02-01

    Over the last decades 3D modelling has been a fast growing field in Geographic Information Science, extensively applied in various domains including reconstruction and visualization of cultural heritage, especially monuments and traditional settlements. Technological advances in computer graphics, allow for modelling of complex 3D objects achieving high precision and accuracy. Procedural modelling is an effective tool and a relatively novel method, based on algorithmic modelling concept. It is utilized for the generation of accurate 3D models and composite facade textures from sets of rules which are called Computer Generated Architecture grammars (CGA grammars), defining the objects' detailed geometry, rather than altering or editing the model manually. In this paper, procedural modelling tools have been exploited to generate the 3D model of a traditional settlement in the region of Central Zagori in Greece. The detailed geometries of 3D models derived from the application of shape grammars on selected footprints, and the process resulted in a final 3D model, optimally describing the built environment of Central Zagori, in three levels of Detail (LoD). The final 3D scene was exported and published as 3D web-scene which can be viewed with 3D CityEngine viewer, giving a walkthrough the whole model, same as in virtual reality or game environments. This research work addresses issues regarding textures' precision, LoD for 3D objects and interactive visualization within one 3D scene, as well as the effectiveness of large scale modelling, along with the benefits and drawbacks that derive from procedural modelling techniques in the field of cultural heritage and more specifically on 3D modelling of traditional settlements.

  6. 3D-2D ultrasound feature-based registration for navigated prostate biopsy: a feasibility study.

    PubMed

    Selmi, Sonia Y; Promayon, Emmanuel; Troccaz, Jocelyne

    2016-08-01

    The aim of this paper is to describe a 3D-2D ultrasound feature-based registration method for navigated prostate biopsy and its first results obtained on patient data. A system combining a low-cost tracking system and a 3D-2D registration algorithm was designed. The proposed 3D-2D registration method combines geometric and image-based distances. After extracting features from ultrasound images, 3D and 2D features within a defined distance are matched using an intensity-based function. The results are encouraging and show acceptable errors with simulated transforms applied on ultrasound volumes from real patients.

  7. Are There Side Effects to Watching 3D Movies? A Prospective Crossover Observational Study on Visually Induced Motion Sickness

    PubMed Central

    Solimini, Angelo G.

    2013-01-01

    Background The increasing popularity of commercial movies showing three dimensional (3D) images has raised concern about possible adverse side effects on viewers. Methods and Findings A prospective carryover observational study was designed to assess the effect of exposure (3D vs. 2D movie views) on self reported symptoms of visually induced motion sickness. The standardized Simulator Sickness Questionnaire (SSQ) was self administered on a convenience sample of 497 healthy adult volunteers before and after the vision of 2D and 3D movies. Viewers reporting some sickness (SSQ total score>15) were 54.8% of the total sample after the 3D movie compared to 14.1% of total sample after the 2D movie. Symptom intensity was 8.8 times higher than baseline after exposure to 3D movie (compared to the increase of 2 times the baseline after the 2D movie). Multivariate modeling of visually induced motion sickness as response variables pointed out the significant effects of exposure to 3D movie, history of car sickness and headache, after adjusting for gender, age, self reported anxiety level, attention to the movie and show time. Conclusions Seeing 3D movies can increase rating of symptoms of nausea, oculomotor and disorientation, especially in women with susceptible visual-vestibular system. Confirmatory studies which include examination of clinical signs on viewers are needed to pursue a conclusive evidence on the 3D vision effects on spectators. PMID:23418530

  8. A 2D 3D registration with low dose radiographic system for in vivo kinematic studies.

    PubMed

    Jerbi, T; Burdin, V; Stindel, E; Roux, C

    2011-01-01

    The knowledge of the poses and the positions of the knee bones and prostheses is of a great interest in the orthopedic and biomechanical applications. In this context, we use an ultra low dose bi-planar radiographic system called EOS to acquire two radiographs of the studied bones in each position. In this paper, we develop a new method for 2D 3D registration based on the frequency domain to determine the poses and the positions during quasi static motion analysis for healthy and prosthetic knees. Data of two healthy knees and four knees with unicompartimental prosthesis performing three different poses (full extension, 30° and 60° of flexion) were used in this work. The results we obtained are in concordance with the clinical accuracy and with the accuracy reported in other previous studies.

  9. Exploring the surface reactivity of 3d metal endofullerenes: a density-functional theory study.

    PubMed

    Estrada-Salas, Rubén E; Valladares, Ariel A

    2009-09-24

    Changes in the preferential sites of electrophilic, nucleophilic, and radical attacks on the pristine C60 surface with endohedral doping using 3d transition metal atoms were studied via two useful reactivity indices, namely the Fukui functions and the molecular electrostatic potential. Both of these were calculated at the density functional BPW91 level of theory with the DNP basis set. Our results clearly show changes in the preferential reactivity sites on the fullerene surface when it is doped with Mn, Fe, Co, or Ni atoms, whereas there are no significant changes in the preferential reactivity sites on the C60 surface upon endohedral doping with Cu and Zn atoms. Electron affinities (EA), ionization potentials (IP), and HOMO-LUMO gaps (Eg) were also calculated to complete the study of the endofullerene's surface reactivity. These findings provide insight into endofullerene functionalization, an important issue in their application.

  10. The QSAR study of flavonoid-metal complexes scavenging rad OH free radical

    NASA Astrophysics Data System (ADS)

    Wang, Bo-chu; Qian, Jun-zhen; Fan, Ying; Tan, Jun

    2014-10-01

    Flavonoid-metal complexes have antioxidant activities. However, quantitative structure-activity relationships (QSAR) of flavonoid-metal complexes and their antioxidant activities has still not been tackled. On the basis of 21 structures of flavonoid-metal complexes and their antioxidant activities for scavenging rad OH free radical, we optimised their structures using Gaussian 03 software package and we subsequently calculated and chose 18 quantum chemistry descriptors such as dipole, charge and energy. Then we chose several quantum chemistry descriptors that are very important to the IC50 of flavonoid-metal complexes for scavenging rad OH free radical through method of stepwise linear regression, Meanwhile we obtained 4 new variables through the principal component analysis. Finally, we built the QSAR models based on those important quantum chemistry descriptors and the 4 new variables as the independent variables and the IC50 as the dependent variable using an Artificial Neural Network (ANN), and we validated the two models using experimental data. These results show that the two models in this paper are reliable and predictable.

  11. The interplay between QSAR/QSPR studies and partial order ranking and formal concept analyses.

    PubMed

    Carlsen, Lars

    2009-04-17

    The often observed scarcity of physical-chemical and well as toxicological data hampers the assessment of potentially hazardous chemicals released to the environment. In such cases Quantitative Structure-Activity Relationships/Quantitative Structure-Property Relationships (QSAR/QSPR) constitute an obvious alternative for rapidly, effectively and inexpensively generatng missing experimental values. However, typically further treatment of the data appears necessary, e.g., to elucidate the possible relations between the single compounds as well as implications and associations between the various parameters used for the combined characterization of the compounds under investigation. In the present paper the application of QSAR/QSPR in combination with Partial Order Ranking (POR) methodologies will be reviewed and new aspects using Formal Concept Analysis (FCA) will be introduced. Where POR constitutes an attractive method for, e.g., prioritizing a series of chemical substances based on a simultaneous inclusion of a range of parameters, FCA gives important information on the implications associations between the parameters. The combined approach thus constitutes an attractive method to a preliminary assessment of the impact on environmental and human health by primary pollutants or possibly by a primary pollutant well as a possible suite of transformation subsequent products that may be both persistent in and bioaccumulating and toxic. The present review focus on the environmental - and human health impact by residuals of the rocket fuel 1,1-dimethylhydrazine (heptyl) and its transformation products as an illustrative example.

  12. The Interplay between QSAR/QSPR Studies and Partial Order Ranking and Formal Concept Analyses

    PubMed Central

    Carlsen, Lars

    2009-01-01

    The often observed scarcity of physical-chemical and well as toxicological data hampers the assessment of potentially hazardous chemicals released to the environment. In such cases Quantitative Structure-Activity Relationships/Quantitative Structure-Property Relationships (QSAR/QSPR) constitute an obvious alternative for rapidly, effectively and inexpensively generatng missing experimental values. However, typically further treatment of the data appears necessary, e.g., to elucidate the possible relations between the single compounds as well as implications and associations between the various parameters used for the combined characterization of the compounds under investigation. In the present paper the application of QSAR/QSPR in combination with Partial Order Ranking (POR) methodologies will be reviewed and new aspects using Formal Concept Analysis (FCA) will be introduced. Where POR constitutes an attractive method for, e.g., prioritizing a series of chemical substances based on a simultaneous inclusion of a range of parameters, FCA gives important information on the implications associations between the parameters. The combined approach thus constitutes an attractive method to a preliminary assessment of the impact on environmental and human health by primary pollutants or possibly by a primary pollutant well as a possible suite of transformation subsequent products that may be both persistent in and bioaccumulating and toxic. The present review focus on the environmental – and human health impact by residuals of the rocket fuel 1,1-dimethylhydrazine (heptyl) and its transformation products as an illustrative example. PMID:19468330

  13. Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

    NASA Astrophysics Data System (ADS)

    Hussain, Abrar; Melville, James L.; Hirst, Jonathan D.

    2010-01-01

    Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide `tail' to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR "coeff*stdev" contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.

  14. Feasibility of a 3D human airway epithelial model to study respiratory absorption.

    PubMed

    Reus, Astrid A; Maas, Wilfred J M; Jansen, Harm T; Constant, Samuel; Staal, Yvonne C M; van Triel, Jos J; Kuper, C Frieke

    2014-03-01

    The respiratory route is an important portal for human exposure to a large variety of substances. Consequently, there is an urgent need for realistic in vitro strategies for evaluation of the absorption of airborne substances with regard to safety and efficacy assessment. The present study investigated feasibility of a 3D human airway epithelial model to study respiratory absorption, in particular to differentiate between low and high absorption of substances. Bronchial epithelial models (MucilAir™), cultured at the air-liquid interface, were exposed to eight radiolabeled model substances via the apical epithelial surface. Absorption was evaluated by measuring radioactivity in the apical compartment, the epithelial cells and the basolateral culture medium. Antipyrine, caffeine, naproxen and propranolol were highly transported across the epithelial cell layer (>5%), whereas atenolol, mannitol, PEG-400 and insulin were limitedly transported (<5%). Results indicate that the 3D human airway epithelial model used in this study is able to differentiate between substances with low and high absorption. The intra-experimental reproducibility of the results was considered adequate based on an average coefficient of variation (CV) of 15%. The inter-experimental reproducibility of highly absorbed compounds was in a similar range (CV of 15%), but this value was considerably higher for those compounds that were limitedly absorbed. No statistical significant differences between different donors and experiments were observed. The present study provides a simple method transposable in any lab, which can be used to rank the absorption of chemicals and pharmaceuticals, and is ready for further validation with respect to reproducibility and capacity of the method to predict respiratory transport in humans.

  15. Study on embedding fiber Bragg grating sensor into the 3D printing structure for health monitoring

    NASA Astrophysics Data System (ADS)

    Li, Ruiya; Tan, Yuegang; Zhou, Zude; Fang, Liang; Chen, Yiyang

    2016-10-01

    3D printing technology is a rapidly developing manufacturing technology, which is known as a core technology in the third industrial revolution. With the continuous improvement of the application of 3D printing products, the health monitoring of the 3D printing structure is particularly important. Fiber Bragg grating (FBG) sensing technology is a new type of optical sensing technology with unique advantages comparing to traditional sensing technology, and it has great application prospects in structural health monitoring. In this paper, the FBG sensors embedded in the internal structure of the 3D printing were used to monitor the static and dynamic strain variation of 3D printing structure during loading process. The theoretical result and experimental result has good consistency and the characteristic frequency detected by FBG sensor is consistent with the testing results of traditional accelerator in the dynamic experiment. The results of this paper preliminary validate that FBG embedded in the 3D printing structure can effectively detecting the static and dynamic stain change of the 3D printing structure, which provide some guidance for the health monitoring of 3D printing structure.

  16. Roughness receptivity studies in a 3-D boundary layer - Flight tests and computations

    NASA Astrophysics Data System (ADS)

    Carpenter, Andrew L.; Saric, William S.; Reed, Helen L.

    The receptivity of 3-D boundary layers to micron-sized, spanwise-periodic Discrete Roughness Elements (DREs) was studied. The DREs were applied to the leading edge of a 30-degree swept-wing at the wavelength of the most unstable disturbance. In this case, calibrated, multi-element hotfilm sensors were used to measure disturbance wall shear stress. The roughness height was varied from 0 to 50 microns. Thus, the disturbance-shear-stress amplitude variations were determined as a function of modulated DRE heights. The computational work was conducted parallel to the flight experiments. The complete viscous flowfield over the O-2 aircraft with the SWIFT model mounted on the port wing store pylon was successfully modeled and validated with the flight data. This highly accurate basic-state solution was incorporated into linear stability calculations and the wave growth associated with the crossflow instability was calculated.

  17. A 3D Numerical Study of Gravitational Instabilities in Young Circumbinary Disks

    NASA Astrophysics Data System (ADS)

    Cai, Kai; Michael, Scott; Durisen, Richard

    2013-07-01

    Gravitational instabilities (GIs) in protoplanetary disks have been suggested as one of the major formation mechanisms of giant planets. Theoretical and computational studies have indicated that certain family of GIs can be excited in a circumbinary disk, which could lead to enhanced protoplanet formation (e.g., Sellwood & Lin 1989, Boss 2006). We have carried out a 3D simulation of a gravitationally unstable circumbinary disk around a young Sun-like star and a 0.02-Msun companion, both inside the central hole of the disk. Here we present a preliminary comparison between this simulation and a similarly simulated circumstellar disk around a solar-mass star but without the low-mass companion. The GIs stimulated by the binary and those that arise spontaneously are quite different in structure and strength. However, no fragmentation is observed, even after many orbital periods as measured in the outer disk.

  18. Study of negative hydrogen ion beam optics using the 3D3V PIC model

    SciTech Connect

    Miyamoto, K.; Nishioka, S.; Goto, I.; Hatayama, A.; Hanada, M.; Kojima, A.

    2015-04-08

    The mechanism of negative ion extraction under real conditions with the complex magnetic field is studied by using the 3D PIC simulation code. The extraction region of the negative ion source for the negative ion based neutral beam injection system in fusion reactors is modelled. It is shown that the E x B drift of electrons is caused by the magnetic filter and the electron suppression magnetic field, and the resultant asymmetry of the plasma meniscus. Furthermore, it is indicated that that the asymmetry of the plasma meniscus results in the asymmetry of negative ion beam profile including the beam halo. It could be demonstrated theoretically that the E x B drift is not significantly weakened by the elastic collisions of the electrons with neutral particles.

  19. An isostatic study of the Karoo basin and underlying lithosphere in 3-D

    NASA Astrophysics Data System (ADS)

    Scheiber-Enslin, Stephanie E.; Ebbing, Jörg; Webb, Susan J.

    2016-08-01

    A 3-D density model of the crust and upper mantle beneath the Karoo basin is presented here. The model is constrained using potential field, borehole and seismic data. Uplift of the basin by the end of the Cretaceous has resulted in an unusually high plateau (>1000 m) covering a large portion of South Africa. Isostatic studies show the topography is largely compensated by changes in Moho depths (˜35 km on-craton and >45 km off-craton) and changes in lithospheric mantle densities between the Kaapvaal Craton and surrounding regions (˜50 kg m-3 increase from on- to off-craton). This density contrast is determined by inverted satellite gravity and gravity gradient data. The highest topography along the edge of the plateau (>1200 m) and a strong Bouguer gravity low over Lesotho, however, can only be explained by a buoyant asthenosphere with a density decrease of around 40 kg m-3.

  20. Uncertainty studies of topographical measurements on steel surface corrosion by 3D scanning electron microscopy.

    PubMed

    Kang, K W; Pereda, M D; Canafoglia, M E; Bilmes, P; Llorente, C; Bonetto, R

    2012-02-01

    Pitting corrosion is a damage mechanism quite serious and dangerous in both carbon steel boiler tubes for power plants which are vital to most industries and stainless steels for orthopedic human implants whose demand, due to the increase of life expectation and rate of traffic accidents, has sharply increased. Reliable methods to characterize this kind of damage are becoming increasingly necessary, when trying to evaluate the advance of damage and to establish the best procedures for component inspection in order to determine remaining lives and failure mitigation. A study about the uncertainties on the topographies of corrosion pits from 3D SEM images, obtained at low magnifications (where errors are greater) and different stage tilt angles were carried out using an in-house software previously developed. Additionally, measurements of pit depths on biomaterial surfaces, subjected to two different surface treatments on stainless steels, were carried out. The different depth distributions observed were in agreement with electrochemical measurements.

  1. Structural and property studies on metal-organic compounds with 3-D supramolecular network

    NASA Astrophysics Data System (ADS)

    Zhang, Qi-Ying; Ma, Ke-Fang; Xiao, Hong-Ping; Li, Xin-Hua; Shi, Qian

    2014-07-01

    Two carboxylato-bridged allomeric compounds, {[Cu2(dbsa)2(hmt) (H2O)4]1/2·2H2O}n (1), {[Ni(dbsa)(H2O)2]1/2[Ni(dbsa)(hmt)(H2O)2]1/2·2H2O}n (2) (H2dbsa=meso-2,3-dibromosuccinic acid, hmt=hexamethylenetetramine) have been synthesized and characterized by X-ray structral analyses. The metal ions have two kinds of coordination fashion in one unit, and bridged by carboxylate and hmt ligands along with weak interactions existing in the solid structure, forming a 3-D supramolecular network. Variable-temperature magnetic property studies reveal the existence of antiferromagnetic interactions in 1 and 2 with g=2.2, J1=-3.5 cm-1, J2=-2.8 cm-1 for 1, and g=2.1, J=-3.5 cm-1 for 2.

  2. Genetic and Environmental Contributions to Facial Morphological Variation: A 3D Population-Based Twin Study

    PubMed Central

    Djordjevic, Jelena; Zhurov, Alexei I.; Richmond, Stephen

    2016-01-01

    Introduction Facial phenotype is influenced by genes and environment; however, little is known about their relative contributions to normal facial morphology. The aim of this study was to assess the relative genetic and environmental contributions to facial morphological variation using a three-dimensional (3D) population-based approach and the classical twin study design. Materials and Methods 3D facial images of 1380 female twins from the TwinsUK Registry database were used. All faces were landmarked, by manually placing 37 landmark points, and Procrustes registered. Three groups of traits were extracted and analysed: 19 principal components (uPC) and 23 principal components (sPC), derived from the unscaled and scaled landmark configurations respectively, and 1275 linear distances measured between 51 landmarks (37 manually identified and 14 automatically calculated). The intraclass correlation coefficients, rMZ and rDZ, broad-sense heritability (h2), common (c2) and unique (e2) environment contributions were calculated for all traits for the monozygotic (MZ) and dizygotic (DZ) twins. Results Heritability of 13 uPC and 17 sPC reached statistical significance, with h2 ranging from 38.8% to 78.5% in the former and 30.5% to 84.8% in the latter group. Also, 1222 distances showed evidence of genetic control. Common environment contributed to one PC in both groups and 53 linear distances (4.3%). Unique environment contributed to 17 uPC and 20 sPC and 1245 distances. Conclusions Genetic factors can explain more than 70% of the phenotypic facial variation in facial size, nose (width, prominence and height), lips prominence and inter-ocular distance. A few traits have shown potential dominant genetic influence: the prominence and height of the nose, the lower lip prominence in relation to the chin and upper lip philtrum length. Environmental contribution to facial variation seems to be the greatest for the mandibular ramus height and horizontal facial asymmetry. PMID

  3. Study of City Landscape Heritage Using Lidar Data and 3d-City Models

    NASA Astrophysics Data System (ADS)

    Rubinowicz, P.; Czynska, K.

    2015-04-01

    In contemporary town planning protection of urban landscape is a significant issue. It regards especially those cities, where urban structures are the result of ages of evolution and layering of historical development process. Specific panoramas and other strategic views with historic city dominants can be an important part of the cultural heritage and genius loci. Other hand, protection of such expositions introduces limitations for future based city development. Digital Earth observation techniques creates new possibilities for more accurate urban studies, monitoring of urbanization processes and measuring of city landscape parameters. The paper examines possibilities of application of Lidar data and digital 3D-city models for: a) evaluation of strategic city views, b) mapping landscape absorption limits, and c) determination protection zones, where the urbanization and buildings height should be limited. In reference to this goal, the paper introduces a method of computational analysis of the city landscape called Visual Protection Surface (VPS). The method allows to emulate a virtual surface above the city including protection of a selected strategic views. The surface defines maximum height of buildings in such a way, that no new facility can be seen in any of selected views. The research includes also analyses of the quality of simulations according the form and precision of the input data: airborne Lidar / DSM model and more advanced 3D-city models (incl. semantic of the geometry, like in CityGML format). The outcome can be a support for professional planning of tall building development. Application of VPS method have been prepared by a computer program developed by the authors (C++). Simulations were carried out on an example of the city of Dresden.

  4. 3D Inversion of complex resistivity data: Case study on Mineral Exploration Site.

    NASA Astrophysics Data System (ADS)

    Son, Jeong-Sul; Kim, Jung-ho; Park, Sam-gyu; Park, My-Kyung

    2016-04-01

    Complex resistivity (CR) method is a frequency domain induced polarization (IP) method. It is also known as Spectral IP (SIP) method, if wider frequencies are used in data acquisition and interpretation. Although it takes more times than conventional time domain IP method, its data quality is more stable because its data acquisition which measures amplitude and phase is done when the source current is being injected. Our research group has been studying the modeling and inversion algorithms of complex resistivity (CR) method since several years ago and recently applied developed algorithms to various real field application. Due to tough terrain in our country, Profile survey and 2D interpretation were generally used. But to get more precise interpretation, three dimensional modeling and inversion algorithm is required. We developed three dimensional inversion algorithm for this purpose. In the inversion, we adopt the method of adaptive lagraingian multiplier which is automatically set based on the size of error misfit and model regularization norm. It was applied on the real data acquired for mineral exploration sites. CR data was acquired with the Zeta system, manufactured by Zonge Co. In the inversion, only the lower frequency data is used considering its quality and developed 3D inversion algorithm was applied to the acquired data set. Its results were compared to those of time domain IP data conducted at the same site. Resistivity image sections of CR and conventional resistivity method were almost identical. Phase anomalies were well matched with chargeability anomalies and the mining history of the test site. Each anomalies were well discriminated in 3D interpretation than those of 2D. From those experiments, we know that CR method was very effective for the mineral exploration.

  5. In Vitro Antioxidant Activity of Selected 4-Hydroxy-chromene-2-one Derivatives—SAR, QSAR and DFT Studies

    PubMed Central

    Mladenović, Milan; Mihailović, Mirjana; Bogojević, Desanka; Matić, Sanja; Nićiforović, Neda; Mihailović, Vladimir; Vuković, Nenad; Sukdolak, Slobodan; Solujić, Slavica

    2011-01-01

    The series of fifteen synthesized 4-hydroxycoumarin derivatives was subjected to antioxidant activity evaluation in vitro, through total antioxidant capacity, 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydroxyl radical, lipid peroxide scavenging and chelating activity. The highest activity was detected during the radicals scavenging, with 2b, 6b, 2c, and 4c noticed as the most active. The antioxidant activity was further quantified by the quantitative structure-activity relationships (QSAR) studies. For this purpose, the structures were optimized using Paramethric Method 6 (PM6) semi-empirical and Density Functional Theory (DFT) B3LYP methods. Bond dissociation enthalpies of coumarin 4-OH, Natural Bond Orbital (NBO) gained hybridization of the oxygen, acidity of the hydrogen atom and various molecular descriptors obtained, were correlated with biological activity, after which we designed 20 new antioxidant structures, using the most favorable structural motifs, with much improved predicted activity in vitro. PMID:21686153

  6. The radiological feature of anterior occiput-to-axis screw fixation as it guides the screw trajectory on 3D printed models: a feasibility study on 3D images and 3D printed models.

    PubMed

    Wu, Ai-Min; Wang, Sheng; Weng, Wan-Qing; Shao, Zhen-Xuan; Yang, Xin-Dong; Wang, Jian-Shun; Xu, Hua-Zi; Chi, Yong-Long

    2014-12-01

    Anterior occiput-to-axis screw fixation is more suitable than a posterior approach for some patients with a history of posterior surgery. The complex osseous anatomy between the occiput and the axis causes a high risk of injury to neurological and vascular structures, and it is important to have an accurate screw trajectory to guide anterior occiput-to-axis screw fixation. Thirty computed tomography (CT) scans of upper cervical spines were obtained for three-dimensional (3D) reconstruction. Cylinders (1.75 mm radius) were drawn to simulate the trajectory of an anterior occiput-to-axis screw. The imitation screw was adjusted to 4 different angles and measured, as were the values of the maximized anteroposterior width and the left-right width of the occiput (C0) to the C1 and C1 to C2 joints. Then, the 3D models were printed, and an angle guide device was used to introduce the screws into the 3D models referring to the angles calculated from the 3D images. We found the screw angle ranged from α1 (left: 4.99±4.59°; right: 4.28±5.45°) to α2 (left: 20.22±3.61°; right: 19.63±4.94°); on the lateral view, the screw angle ranged from β1 (left: 13.13±4.93°; right: 11.82±5.64°) to β2 (left: 34.86±6.00°; right: 35.01±5.77°). No statistically significant difference was found between the data of the left and right sides. On the 3D printed models, all of the anterior occiput-to-axis screws were successfully introduced, and none of them penetrated outside of the cortex; the mean α4 was 12.00±4.11 (left) and 12.25±4.05 (right), and the mean β4 was 23.44±4.21 (left) and 22.75±4.41 (right). No significant difference was found between α4 and β4 on the 3D printed models and α3 and β3 calculated from the 3D digital images of the left and right sides. Aided with the angle guide device, we could achieve an optimal screw trajectory for anterior occiput-to-axis screw fixation on 3D printed C0 to C2 models.

  7. Study on the Construction and Application of 3D Geographic Information Services for the Smart City

    NASA Astrophysics Data System (ADS)

    Mao, W.-Q.

    2014-04-01

    Smart City, whose main characteristics are intelligence and interconnection capability, has become an important goal of some cities' development. This paper, based on urban three-dimensional geographic information characteristics, analyses 3D geographic information requirements in the Smart City construction and development process, proposes construction and management methods for 3D geographic information. Furthermore, this paper takes Shanghai Geographic Information Public Service Platform as an example, discusses 3D geographic information application in multiple fields, and proves that it is an effective ways to promote Intelligent City construction.

  8. The applicability of 3D Doppler tomography to studies of polars

    NASA Astrophysics Data System (ADS)

    Kononov, D. A.; Agafonov, M. I.; Sharova, O. I.; Bisikalo, D. V.; Zhilkin, A. G.; Sidorov, M. Yu.

    2014-12-01

    The applicability of 3D Doppler tomography to mapping gas flows in polars is considered. Synthetic profiles of emission lines are calculated using solutions (for the densities, temperatures, and velocity components) obtained from 3D MHD modeling, which are then used to construct 3D Doppler tomograms in the velocity space ( V x , V y , V z ). Subsequent analysis of these tomograms applying observational constraints (the signal-to-noise ratio, number of input profiles, etc.) enables evaluation of limits to the method's applicability.

  9. Profile-QSAR: a novel meta-QSAR method that combines activities across the kinase family to accurately predict affinity, selectivity, and cellular activity.

    PubMed

    Martin, Eric; Mukherjee, Prasenjit; Sullivan, David; Jansen, Johanna

    2011-08-22

    Profile-QSAR is a novel 2D predictive model building method for kinases. This "meta-QSAR" method models the activity of each compound against a new kinase target as a linear combination of its predicted activities against a large panel of 92 previously studied kinases comprised from 115 assays. Profile-QSAR starts with a sparse incomplete kinase by compound (KxC) activity matrix, used to generate Bayesian QSAR models for the 92 "basis-set" kinases. These Bayesian QSARs generate a complete "synthetic" KxC activity matrix of predictions. These synthetic activities are used as "chemical descriptors" to train partial-least squares (PLS) models, from modest amounts of medium-throughput screening data, for predicting activity against new kinases. The Profile-QSAR predictions for the 92 kinases (115 assays) gave a median external R²(ext) = 0.59 on 25% held-out test sets. The method has proven accurate enough to predict pairwise kinase selectivities with a median correlation of R²(ext) = 0.61 for 958 kinase pairs with at least 600 common compounds. It has been further expanded by adding a "C(k)XC" cellular activity matrix to the KxC matrix to predict cellular activity for 42 kinase driven cellular assays with median R²(ext) = 0.58 for 24 target modulation assays and R²(ext) = 0.41 for 18 cell proliferation assays. The 2D Profile-QSAR, along with the 3D Surrogate AutoShim, are the foundations of an internally developed iterative medium-throughput screening (IMTS) methodology for virtual screening (VS) of compound archives as an alternative to experimental high-throughput screening (HTS). The method has been applied to 20 actual prospective kinase projects. Biological results have so far been obtained in eight of them. Q² values ranged from 0.3 to 0.7. Hit-rates at 10 uM for experimentally tested compounds varied from 25% to 80%, except in K5, which was a special case aimed specifically at finding "type II" binders, where none of the compounds were predicted to be

  10. QSAR studies of bioconcentration factors of polychlorinated biphenyls (PCBs) using DFT, PCS and CoMFA.

    PubMed

    Liu, Hui; Liu, Hongxia; Sun, Ping; Wang, Zunyao

    2014-11-01

    The bioconcentration factors (BCFs) of 58 polychlorinated biphenyls (PCBs) were modeled by quantitative structure-activity relationship (QSAR) using density functional theory (DFT), the position of Cl substitution (PCS) and comparative molecular field analysis (CoMFA) methods. All the models were robust and predictive, and especially, the best CoMFA model was significant with a correlation coefficient (R(2)) of 0.926, a cross-validation correlation coefficient (Q(2)) of 0.821 and a root mean square error estimated (RMSE) of 0.235. The results indicate that the electrostatic descriptors play a more significant role in BCFs of PCBs. Additionally, a test set was used to compare the predictive ability of our models to others, and results show that our CoMFA model present the lowest RMSE. Thus, the models obtain in this work can be used to predict the BCFs of remaining 152 PCBs without available experimental values.

  11. Evolution of 3-D geologic framework modeling and its application to groundwater flow studies

    USGS Publications Warehouse

    Blome, Charles D.; Smith, David V.

    2012-01-01

    In this Fact Sheet, the authors discuss the evolution of project 3-D subsurface framework modeling, research in hydrostratigraphy and airborne geophysics, and methodologies used to link geologic and groundwater flow models.

  12. EMPulse, a new 3-D simulation code for electromagnetic pulse studies

    NASA Astrophysics Data System (ADS)

    Cohen, Bruce; Eng, Chester; Farmer, William; Friedman, Alex; Grote, David; Kruger, Hans; Larson, David

    2016-10-01

    EMPulse is a comprehensive and modern 3-D simulation code for electro-magnetic pulse (EMP) formation and propagation studies, being developed at LLNL as part of a suite of codes to study E1 EMP originating from prompt gamma rays. EMPulse builds upon the open-source Warp particle-in-cell code framework developed by members of this team and collaborators at other institutions. The goal of this endeavor is a new tool enabling the detailed and self-consistent study of multi-dimensional effects in geometries that have typically been treated only approximately. Here we present an overview of the project, the models and methods that have been developed and incorporated into EMPulse, tests of these models, comparisons to simulations undertaken in CHAP-lite (derived from the legacy code CHAP due to C. Longmire and co-workers), and some approaches to increased computational efficiency being studied within our project. This work was performed under the auspices of the U.S. DOE by Lawrence Livermore National Security, LLC, Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344.

  13. 3D high-resolution two-photon crosslinked hydrogel structures for biological studies.

    PubMed

    Brigo, Laura; Urciuolo, Anna; Giulitti, Stefano; Giustina, Gioia Della; Tromayer, Maximilian; Liska, Robert; Elvassore, Nicola; Brusatin, Giovanna

    2017-03-25

    Hydrogels are widely used as matrices for cell growth due to the their tuneable chemical and physical properties, which mimic the extracellular matrix of natural tissue. The microfabrication of hydrogels into arbitrarily complex 3D structures is becoming essential for numerous biological applications, and in particular for investigating the correlation between cell shape and cell function in a 3D environment. Micrometric and sub-micrometric resolution hydrogel scaffolds are required to deeply investigate molecular mechanisms behind cell-matrix interaction and downstream cellular processes. We report the design and development of high resolution 3D gelatin hydrogel woodpile structures by two-photon crosslinking. Hydrated structures of lateral linewidth down to 0.5 µm, lateral and axial resolution down to a few µm are demonstrated. According to the processing parameters, different degrees of polymerization are obtained, resulting in hydrated scaffolds of variable swelling and deformation. The 3D hydrogels are biocompatible and promote cell adhesion and migration. Interestingly, according to the polymerization degree, 3D hydrogel woodpile structures show variable extent of cell adhesion and invasion. Human BJ cell lines show capability of deforming 3D micrometric resolved hydrogel structures.

  14. NEW 3D TECHNIQUES FOR RANKING AND PRIORITIZATION OF CHEMICAL INVENTORIES

    EPA Science Inventory

    New three-dimensional quantitative structure activity (3-D QSAR) techniques for prioritizing chemical inventories for endocrine activity will be presented. The Common Reactivity Pattern (COREPA) approach permits identification of common steric and/or electronic patterns associate...

  15. Uncertainty in QSAR predictions.

    PubMed

    Sahlin, Ullrika

    2013-03-01

    It is relevant to consider uncertainty in individual predictions when quantitative structure-activity (or property) relationships (QSARs) are used to support decisions of high societal concern. Successful communication of uncertainty in the integration of QSARs in chemical safety assessment under the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system can be facilitated by a common understanding of how to define, characterise, assess and evaluate uncertainty in QSAR predictions. A QSAR prediction is, compared to experimental estimates, subject to added uncertainty that comes from the use of a model instead of empirically-based estimates. A framework is provided to aid the distinction between different types of uncertainty in a QSAR prediction: quantitative, i.e. for regressions related to the error in a prediction and characterised by a predictive distribution; and qualitative, by expressing our confidence in the model for predicting a particular compound based on a quantitative measure of predictive reliability. It is possible to assess a quantitative (i.e. probabilistic) predictive distribution, given the supervised learning algorithm, the underlying QSAR data, a probability model for uncertainty and a statistical principle for inference. The integration of QSARs into risk assessment may be facilitated by the inclusion of the assessment of predictive error and predictive reliability into the "unambiguous algorithm", as outlined in the second OECD principle.

  16. In Silico Drug-Designing Studies on Flavanoids as Anticolon Cancer Agents: Pharmacophore Mapping, Molecular Docking, and Monte Carlo Method-Based QSAR Modeling.

    PubMed

    Simon, Lalitha; Imane, Abdelli; Srinivasan, K K; Pathak, Lokesh; Daoud, I

    2016-04-08

    In silico molecular modeling studies were carried out on some newly synthesized flavanoid analogues. Search for potential targets for these compounds was performed using pharmacophore-mapping algorithm employing inverse screening of some representative compounds to a large set of pharmacophore models constructed from human target proteins. Further, molecular docking studies were carried out to assess binding affinity of these compounds to proteins mediating tumor growth. In vitro anticancer studies were carried out on colon cancer cell lines (HCT116) to assess validity of this approach for target identification of the new compounds. Further important structural features of compounds for anticolon cancer activity were assessed using Monte Carlo-based SMILES and hydrogen graph-Based QSAR studies. In conclusion this study have depicted successful and stepwise application of pharmacophore mapping, molecular docking, and QSAR studies in target identification and lead optimization of flavonoids.

  17. Comparative study of DSC-PWI and 3D-ASL in ischemic stroke patients.

    PubMed

    Zhang, Shui-xia; Yao, Yi-hao; Zhang, Shun; Zhu, Wen-jie; Tang, Xiang-yu; Qin, Yuan-yuan; Zhao, Ling-yun; Liu, Cheng-xia; Zhu, Wen-zhen

    2015-12-01

    The purpose of this study was to quantitatively analyze the relationship between three dimensional arterial spin labeling (3D-ASL) and dynamic susceptibility contrast-enhanced perfusion weighted imaging (DSC-PWI) in ischemic stroke patients. Thirty patients with ischemic stroke were included in this study. All subjects underwent routine magnetic resonance imaging scanning, diffusion weighted imaging (DWI), magnetic resonance angiography (MRA), 3D-ASL and DSC-PWI on a 3.0T MR scanner. Regions of interest (ROIs) were drawn on the cerebral blood flow (CBF) maps (derived from ASL) and multi-parametric DSC perfusion maps, and then, the absolute and relative values of ASL-CBF, DSC-derived CBF, and DSC-derived mean transit time (MTT) were calculated. The relationships between ASL and DSC parameters were analyzed using Pearson's correlation analysis. Receiver operative characteristic (ROC) curves were performed to define the thresholds of relative value of ASL-CBF (rASL) that could best predict DSC-CBF reduction and MTT prolongation. Relative ASL better correlated with CBF and MTT in the anterior circulation with the Pearson correlation coefficients (R) values being 0.611 (P<0.001) and-0.610 (P<0.001) respectively. ROC curves demonstrated that when rASL ≤0.585, the sensitivity, specificity and accuracy for predicting ROIs with rCBF<0.9 were 92.3%, 63.6% and 76.6% respectively. When rASL ≤0.952, the sensitivity, specificity and accuracy for predicting ROIs rMTT>1.0 were 75.7%, 89.2% and 87.8% respectively. ASL-CBF map has better linear correlations with DSC-derived parameters (DSC-CBF and MTT) in anterior circulation in ischemic stroke patients. Additionally, when rASL is lower than 0.585, it could predict DSC-CBF decrease with moderate accuracy. If rASL values range from 0.585 to 0.952, we just speculate the prolonged MTT.

  18. Feasibility study of 3D cardiac imaging using a portable conebeam scanner

    NASA Astrophysics Data System (ADS)

    Petrov, Ivailo; Helm, Patrick A.; Drangova, Maria

    2012-03-01

    While the Medtronic O-arm was developed for image-guidance applications during orthopedic procedures, it has potential to assist in cardiac surgical and electrophysiological applications; the purpose of this study was to evaluate the feasibility of using a mobile conebeam imaging system (O-arm) for gated cardiac imaging. In an in vivo study (two pigs), projection data from four independently acquired breath-held scans were combined to obtain cardiac gated 3D images. Projection images were acquired during the infusion of contrast agent and while tracking the ECG. Both standard and high-definition modes of the O-arm were evaluated. Projection data were retrospectively combined to generate images corresponding to systole and diastole; different acceptance windows were investigated. The contrast to noise ratio (CNR) between blood and myocardium was compared for the different gating strategies. Gated cardiac images were successfully reconstructed with as few as two scans combined (CNR = 2.5) and a window of 200 ms. Improved image quality was achieved when selecting views based on the minimum time from the selected phase point in the cardiac cycle, rather than a fixed window; in this case the effective temporal window increased to 475 ms for two scans. The O-arm has the potential to be used as a mobile cardiac imaging system, capable of three-dimensional imaging.

  19. 3D Printing Surgical Implants at the clinic: A Experimental Study on Anterior Cruciate Ligament Reconstruction.

    PubMed

    Liu, An; Xue, Guang-huai; Sun, Miao; Shao, Hui-feng; Ma, Chi-yuan; Gao, Qing; Gou, Zhong-ru; Yan, Shi-gui; Liu, Yan-ming; He, Yong

    2016-02-15

    Desktop three-dimensional (3D) printers (D3DPs) have become a popular tool for fabricating personalized consumer products, favored for low cost, easy operation, and other advantageous qualities. This study focused on the potential for using D3DPs to successfully, rapidly, and economically print customized implants at medical clinics. An experiment was conducted on a D3DP-printed anterior cruciate ligament surgical implant using a rabbit model. A well-defined, orthogonal, porous PLA screw-like scaffold was printed, then coated with hydroxyapatite (HA) to improve its osteoconductivity. As an internal fixation as well as an ideal cell delivery system, the osteogenic scaffold loaded with mesenchymal stem cells (MSCs) were evaluated through both in vitro and in vivo tests to observe bone-ligament healing via cell therapy. The MSCs suspended in Pluronic F-127 hydrogel on PLA/HA screw-like scaffold showed the highest cell proliferation and osteogenesis in vitro. In vivo assessment of rabbit anterior cruciate ligament models for 4 and 12 weeks showed that the PLA/HA screw-like scaffold loaded with MSCs suspended in Pluronic F-127 hydrogel exhibited significant bone ingrowth and bone-graft interface formation within the bone tunnel. Overall, the results of this study demonstrate that fabricating surgical implants at the clinic (fab@clinic) with D3DPs can be feasible, effective, and economical.

  20. A 3D velocimetry study of the flow through prosthetic heart valves

    NASA Astrophysics Data System (ADS)

    Ledesma, R.; Zenit, R.; Pulos, G.; Sanchez, E.; Juarez, A.

    2006-11-01

    Blood damage commonly appears in medical valve prothesis. It is a mayor concern for the designers and surgeons. It is well known that this damage and other complications result from the modified fluid dynamics through the replacement valve. To evaluate the performance of prosthetic heart valves, it is necessary to study the flow through them. To conduct this study , we have built a flow channel that emulates cardiac conditions and allows optical access such that a 3D-PIV velocimetry system could be used. The experiments are aimed to reconstruct the downstream structure of the flow through a mechanical and a bio-material tricuspid heart valve prothesis. Preliminary results show that the observed coherent structures can be related with haemolysis and trombosis, illnesses commonly found in valve prothesis recipients. The mean flow, the levels of strain rate and the turbulence intensity generated by the valves can also be directly related to blood damage. In general, bio-material made valves tend to reduce these complications.

  1. Potentiometric and spectroscopic study of the interaction of 3d transition metal ions with inositol hexakisphosphate

    NASA Astrophysics Data System (ADS)

    Veiga, Nicolás; Macho, Israel; Gómez, Kerman; González, Gabriel; Kremer, Carlos; Torres, Julia

    2015-10-01

    Among myo-inositol phosphates, the most abundant in nature is the myo-inositol hexakisphosphate, InsP6. Although it is known to be vital to cell functioning, the biochemical research into its metabolism needs chemical and structural analysis of all the protonation, complexation and precipitation processes that it undergoes in the biological media. In view of its high negative charge at physiological level, our group has been leading a thorough research into the InsP6 chemical and structural behavior in the presence of the alkali and alkaline earth metal ions essential for life. The aim of this article is to extend these studies, dealing with the chemical and structural features of the InsP6 interaction with biologically relevant 3d transition metal ions (Fe(II), Fe(III), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II)), in a non-interacting medium and under simulated physiological conditions. The metal-complex stability constants were determined by potentiometry, showing under ligand-excess conditions the formation of mononuclear species in different protonation states. Under metal ion excess, polymetallic species were detected for Fe(II), Fe(III), Zn(II) and Cu(II). Additionally, the 31P NMR and UV-vis spectroscopic studies provided interesting structural aspects of the strong metal ion-InsP6 interaction.

  2. 3D Printing Surgical Implants at the clinic: A Experimental Study on Anterior Cruciate Ligament Reconstruction

    PubMed Central

    Liu, An; Xue, Guang-huai; Sun, Miao; Shao, Hui-feng; Ma, Chi-yuan; Gao, Qing; Gou, Zhong-ru; Yan, Shi-gui; Liu, Yan-ming; He, Yong

    2016-01-01

    Desktop three-dimensional (3D) printers (D3DPs) have become a popular tool for fabricating personalized consumer products, favored for low cost, easy operation, and other advantageous qualities. This study focused on the potential for using D3DPs to successfully, rapidly, and economically print customized implants at medical clinics. An experiment was conducted on a D3DP-printed anterior cruciate ligament surgical implant using a rabbit model. A well-defined, orthogonal, porous PLA screw-like scaffold was printed, then coated with hydroxyapatite (HA) to improve its osteoconductivity. As an internal fixation as well as an ideal cell delivery system, the osteogenic scaffold loaded with mesenchymal stem cells (MSCs) were evaluated through both in vitro and in vivo tests to observe bone-ligament healing via cell therapy. The MSCs suspended in Pluronic F-127 hydrogel on PLA/HA screw-like scaffold showed the highest cell proliferation and osteogenesis in vitro. In vivo assessment of rabbit anterior cruciate ligament models for 4 and 12 weeks showed that the PLA/HA screw-like scaffold loaded with MSCs suspended in Pluronic F-127 hydrogel exhibited significant bone ingrowth and bone-graft interface formation within the bone tunnel. Overall, the results of this study demonstrate that fabricating surgical implants at the clinic (fab@clinic) with D3DPs can be feasible, effective, and economical. PMID:26875826

  3. 3D dynamic rupture simulation and local tomography studies following the 2010 Haiti earthquake

    NASA Astrophysics Data System (ADS)

    Douilly, Roby

    temporary station deployments. We only considered events that had at least 6 P and 6 S arrivals, and an azimuthal gap less then 180 degrees, to simultaneously invert for hypocenters and 3D velocity structure in southern Haiti. We used the program VELEST to define a minimum 1D velocity model, which was then used as a starting model in the computer algorithm SIMULPS14 to produce the 3D tomography. Our results show a pronounced low velocity zone across the Logne fault, which is consistent with the sedimentary basin location from the geologic map. We also observe a southeast low velocity zone, which is consistent with a predefined structure in the morphology. Low velocity structure usually correlates with broad zones of deformation, such as the presence of cracks or faults, or from the presence of fluid in the crust. This work provides information that can be used in future studies focusing on how changes in material properties can affect rupture propagation, which is useful to assess the seismic hazard that Haiti and other regions are facing.

  4. 3D Airborne Electromagnetic Inversion: A case study from the Musgrave Region, South Australia

    NASA Astrophysics Data System (ADS)

    Cox, L. H.; Wilson, G. A.; Zhdanov, M. S.; Sunwall, D. A.

    2012-12-01

    Geophysicists know and accept that geology is inherently 3D, and is resultant from complex, overlapping processes related to genesis, metamorphism, deformation, alteration, weathering, and/or hydrogeology. Yet, the geophysics community has long relied on qualitative analysis, conductivity depth imaging (CDIs), 1D inversion, and/or plate modeling. There are many reasons for this deficiency, not the least of which has been the lack of capacity for historic 3D AEM inversion algorithms to invert entire surveys so as to practically affect exploration decisions. Our recent introduction of a moving sensitivity domain (footprint) methodology has been a paradigm shift in AEM interpretation. The basis of this method is that one needs only to calculate the responses and sensitivities for that part of the 3D earth model that is within the AEM system's sensitivity domain (footprint), and then superimpose all sensitivity domains into a single, sparse sensitivity matrix for the entire 3D earth model which is then updated in a regularized inversion scheme. This has made it practical to rigorously invert entire surveys with thousands of line kilometers of AEM data to mega-cell 3D models in hours using multi-processor workstations. Since 2010, over eighty individual projects have been completed for Aerodat, AEROTEM, DIGHEM, GEOTEM, HELITEM, HoisTEM, MEGATEM, RepTEM, RESOLVE, SkyTEM, SPECTREM, TEMPEST, and VTEM data from Australia, Brazil, Canada, Finland, Ghana, Peru, Tanzania, the US, and Zambia. Examples of 3D AEM inversion have been published for a variety of applications, including mineral exploration, oil sands exploration, salinity, permafrost, and bathymetry mapping. In this paper, we present a comparison of 3D inversions for SkyTEM, SPECTREM, TEMPET and VTEM data acquired over the same area in the Musgrave region of South Australia for exploration under cover.

  5. Hepatic 3D spheroid models for the detection and study of compounds with cholestatic liability

    PubMed Central

    Hendriks, Delilah F. G.; Fredriksson Puigvert, Lisa; Messner, Simon; Mortiz, Wolfgang; Ingelman-Sundberg, Magnus

    2016-01-01

    Drug-induced cholestasis (DIC) is poorly understood and its preclinical prediction is mainly limited to assessing the compound’s potential to inhibit the bile salt export pump (BSEP). Here, we evaluated two 3D spheroid models, one from primary human hepatocytes (PHH) and one from HepaRG cells, for the detection of compounds with cholestatic liability. By repeatedly co-exposing both models to a set of compounds with different mechanisms of hepatotoxicity and a non-toxic concentrated bile acid (BA) mixture for 8 days we observed a selective synergistic toxicity of compounds known to cause cholestatic or mixed cholestatic/hepatocellular toxicity and the BA mixture compared to exposure to the compounds alone, a phenomenon that was more pronounced after extending the exposure time to 14 days. In contrast, no such synergism was observed after both 8 and 14 days of exposure to the BA mixture for compounds that cause non-cholestatic hepatotoxicity. Mechanisms behind the toxicity of the cholestatic compound chlorpromazine were accurately detected in both spheroid models, including intracellular BA accumulation, inhibition of ABCB11 expression and disruption of the F-actin cytoskeleton. Furthermore, the observed synergistic toxicity of chlorpromazine and BA was associated with increased oxidative stress and modulation of death receptor signalling. Combined, our results demonstrate that the hepatic spheroid models presented here can be used to detect and study compounds with cholestatic liability. PMID:27759057

  6. Experiments and parametric studies on 3D metallic auxetic metamaterials with tuneable mechanical properties

    NASA Astrophysics Data System (ADS)

    Ren, Xin; Shen, Jianhu; Ghaedizadeh, Arash; Tian, Hongqi; Xie, Yi Min

    2015-09-01

    Auxetic metamaterials are synthetic materials with microstructures engineered to achieve negative Poisson’s ratios. Auxetic metamaterials are of great interest because of their unusual properties and various potential applications. However, most of the previous research has been focused on auxetic behaviour of elastomers under elastic deformation. Inspired by our recent finding of the loss of auxetic behaviour in metallic auxetic metamaterials, a systematic experimental and numerical investigation has been carried out to explore the mechanism behind this phenomenon. Using an improved methodology of generating buckling-induced auxetic metamaterials, several samples of metallic auxetic metamaterials have been fabricated using a 3D printing technique. The experiments on those samples have revealed the special features of auxetic behaviour for metallic auxetic metamaterials and proved the effectiveness of our structural modification. Parametric studies have been performed through experimentally validated finite element models to explore the auxetic performance of the designed metallic metamaterials. It is found that the auxetic performance can be tuned by the geometry of microstructures, and the strength and stiffness can be tuned by the plasticity of the base material while maintaining the auxetic performance.

  7. 3D Finite Element Study on: Bar Splinted Implants Supporting Partial Denture in the Reconstructed Mandible

    PubMed Central

    El-Anwar, Mohamed; Ghali, Rami; Aboelnagga, Mona

    2016-01-01

    AIM: This study aimed to estimate the stress patterns induced by the masticatory loads on a removable prosthesis supported and retained by bar splinted implants placed in the reconstructed mandible with two different clip materials and without clip, in the fibula-jaw bone and prosthesis using finite element analysis. METHODS: Two 3D finite element models were constructed, that models components were modeled on commercial CAD/CAM software then assembled into finite element package. Vertical loads were applied simulating the masticatory forces unilaterally in the resected site and bilaterally in the central fossa of the lower first molar as 100N (tension and compression). Analysis was based on the assumption full osseointegration between different types of bones, and between implants and fibula while fixing the top surface of the TMJ in place. RESULTS: The metallic bar connecting the three implants is insensitive to the clips material. Its supporting implants showed typical behavior with maximum stress values at the neck region. Fibula and jaw bone showed stresses within physiologic, while clips material effect seems to be very small due to its relatively small size. CONCLUSION: Switching loading force direction from tensile to compression did-not change the stresses and deformations distribution, but reversed their sign from positive to negative. PMID:27275353

  8. Photoemission studies on the 3D Dirac semiemtal state in Na3Bi

    NASA Astrophysics Data System (ADS)

    Xu, Suyang; Chang, Liu; Kushwaha, Satya K.; Sankar, Raman; Krizan, Jason W.; Belopolski, Ilya; Neupane, Madhab; Bian, Guang; Alidoust, Nasser; Chang, Tay-Rong; Jeng, Horng-Tay; Huang, Cheng-Yi; Tsai, Wei-Feng; Lin, Hsin; Shibayev, Pavel P.; Chou, Fangcheng; Cava, Robert J.; Hasan, M. Zahid

    2015-03-01

    A three-dimensional Dirac semimetal is a novel state of matter that has recently attracted interest in condensed matter physics and materials science. We present electronic structure measurements on the (100) surface of a recently discovered Dirac semimetal material Na3Bi. Our experimental data, for the first time, reveal a Lifshitz transition between the two bulk Dirac cones in the bulk band structure of Na3Bi. These results identify the first example of a band structure singularity in 3D Dirac materials. This is in contrast to its 2D analogs such as in twisted bilayer graphene or the surface states of topological crystalline insulators, which have been studied extensively. The observation of multiple bulk Dirac nodes along the rotational crystal axis away from the Kramers point also serve as a signature for the symmetry-protected nature of the Dirac semimetal state in Na3Bi as elaborated in recent theories. The work at Princeton and Princeton-led synchrotron-based ARPES measurements is supported by U.S. DOE DE-FG-02-05ER46200.

  9. FUN3D Grid Refinement and Adaptation Studies for the Ares Launch Vehicle

    NASA Technical Reports Server (NTRS)

    Bartels, Robert E.; Vasta, Veer; Carlson, Jan-Renee; Park, Mike; Mineck, Raymond E.

    2010-01-01

    This paper presents grid refinement and adaptation studies performed in conjunction with computational aeroelastic analyses of the Ares crew launch vehicle (CLV). The unstructured grids used in this analysis were created with GridTool and VGRID while the adaptation was performed using the Computational Fluid Dynamic (CFD) code FUN3D with a feature based adaptation software tool. GridTool was developed by ViGYAN, Inc. while the last three software suites were developed by NASA Langley Research Center. The feature based adaptation software used here operates by aligning control volumes with shock and Mach line structures and by refining/de-refining where necessary. It does not redistribute node points on the surface. This paper assesses the sensitivity of the complex flow field about a launch vehicle to grid refinement. It also assesses the potential of feature based grid adaptation to improve the accuracy of CFD analysis for a complex launch vehicle configuration. The feature based adaptation shows the potential to improve the resolution of shocks and shear layers. Further development of the capability to adapt the boundary layer and surface grids of a tetrahedral grid is required for significant improvements in modeling the flow field.

  10. Mimicking Natural Laminar to Turbulent Flow Transition: A Systematic CFD Study Using PAB3D

    NASA Technical Reports Server (NTRS)

    Pao, S. Paul; Abdol-Hamid, Khaled S.

    2005-01-01

    For applied aerodynamic computations using a general purpose Navier-Stokes code, the common practice of treating laminar to turbulent flow transition over a non-slip surface is somewhat arbitrary by either treating the entire flow as turbulent or forcing the flow to undergo transition at given trip locations in the computational domain. In this study, the possibility of using the PAB3D code, standard k-epsilon turbulence model, and the Girimaji explicit algebraic stresses model to mimic natural laminar to turbulent flow transition was explored. The sensitivity of flow transition with respect to two limiters in the standard k-epsilon turbulence model was examined using a flat plate and a 6:1 aspect ratio prolate spheroid for our computations. For the flat plate, a systematic dependence of transition Reynolds number on background turbulence intensity was found. For the prolate spheroid, the transition patterns in the three-dimensional boundary layer at different flow conditions were sensitive to the free stream turbulence viscosity limit, the reference Reynolds number and the angle of attack, but not to background turbulence intensity below a certain threshold value. The computed results showed encouraging agreements with the experimental measurements at the corresponding geometry and flow conditions.

  11. 3D structures of individual mammalian genomes studied by single-cell Hi-C.

    PubMed

    Stevens, Tim J; Lando, David; Basu, Srinjan; Atkinson, Liam P; Cao, Yang; Lee, Steven F; Leeb, Martin; Wohlfahrt, Kai J; Boucher, Wayne; O'Shaughnessy-Kirwan, Aoife; Cramard, Julie; Faure, Andre J; Ralser, Meryem; Blanco, Enrique; Morey, Lluis; Sansó, Miriam; Palayret, Matthieu G S; Lehner, Ben; Di Croce, Luciano; Wutz, Anton; Hendrich, Brian; Klenerman, Dave; Laue, Ernest D

    2017-04-06

    The folding of genomic DNA from the beads-on-a-string-like structure of nucleosomes into higher-order assemblies is crucially linked to nuclear processes. Here we calculate 3D structures of entire mammalian genomes using data from a new chromosome conformation capture procedure that allows us to first image and then process single cells. The technique enables genome folding to be examined at a scale of less than 100 kb, and chromosome structures to be validated. The structures of individual topological-associated domains and loops vary substantially from cell to cell. By contrast, A and B compartments, lamina-associated domains and active enhancers and promoters are organized in a consistent way on a genome-wide basis in every cell, suggesting that they could drive chromosome and genome folding. By studying genes regulated by pluripotency factor and nucleosome remodelling deacetylase (NuRD), we illustrate how the determination of single-cell genome structure provides a new approach for investigating biological processes.

  12. Thermocapillary bubble flow and coalescence in a rotating cylinder: A 3D study

    NASA Astrophysics Data System (ADS)

    Alhendal, Yousuf; Turan, A.; Al-mazidi, M.

    2015-12-01

    The process of thermocapillary bubbles rising in a rotating 3D cylinder in zero gravity was analysed and presented numerically with the aid of computational fluid dynamics (CFD) by means of the volume of fluid (VOF) method. Calculations were carried out to investigate in detail the effect of the rotational speed of the hosted liquid on the trajectory of both single and group bubbles driven by the Marangoni force in zero-gravity conditions. For rotational speeds from 0.25 to 2 rad/s, bubble displacement with angular motion was found to be directed between the hotter surface and the rotational axis. This is contrary to the conventional bubble flow from areas of high pressure to low pressure, radial direction, or from cold to hot regions, axial direction. The results demonstrate that for the ratio of rotational speeds to the thermocapillary bubble velocity larger than unity, the surface tension gradient is the dominant force and the bubble motion towards the hotter. On the other hand, for ratio less than 1, the bubble motion is dominated and is significantly affected by centrifugal force. As rotation speed increases, the amount of deflection increases and the Marangoni effect vanishes. The current study is novel in the sense that single- and multi-bubble motion incorporating thermocapillary forces in a rotating liquid in a zero-gravity environment has never been numerically investigated.

  13. Study of a high-resolution, 3D positioning cadmium zinc telluride detector for PET

    NASA Astrophysics Data System (ADS)

    Gu, Y.; Matteson, J. L.; Skelton, R. T.; Deal, A. C.; Stephan, E. A.; Duttweiler, F.; Gasaway, T. M.; Levin, C. S.

    2011-03-01

    This paper investigates the performance of 1 mm resolution cadmium zinc telluride (CZT) detectors for positron emission tomography (PET) capable of positioning the 3D coordinates of individual 511 keV photon interactions. The detectors comprise 40 mm × 40 mm × 5 mm monolithic CZT crystals that employ a novel cross-strip readout with interspersed steering electrodes to obtain high spatial and energy resolution. The study found a single anode FWHM energy resolution of 3.06 ± 0.39% at 511 keV throughout most of the detector volume. Improved resolution is expected with properly shielded front-end electronics. Measurements made using a collimated beam established the efficacy of the steering electrodes in facilitating enhanced charge collection across anodes, as well as a spatial resolution of 0.44 ± 0.07 mm in the direction orthogonal to the electrode planes. Finally, measurements based on coincidence electronic collimation yielded a point spread function with 0.78 ± 0.10 mm FWHM, demonstrating 1 mm spatial resolution capability transverse to the anodes—as expected from the 1 mm anode pitch. These findings indicate that the CZT-based detector concept has excellent performance and shows great promise for a high-resolution PET system.

  14. Study of a high-resolution, 3D positioning cadmium zinc telluride detector for PET.

    PubMed

    Gu, Y; Matteson, J L; Skelton, R T; Deal, A C; Stephan, E A; Duttweiler, F; Gasaway, T M; Levin, C S

    2011-03-21

    This paper investigates the performance of 1 mm resolution cadmium zinc telluride (CZT) detectors for positron emission tomography (PET) capable of positioning the 3D coordinates of individual 511 keV photon interactions. The detectors comprise 40 mm × 40 mm × 5 mm monolithic CZT crystals that employ a novel cross-strip readout with interspersed steering electrodes to obtain high spatial and energy resolution. The study found a single anode FWHM energy resolution of 3.06 ± 0.39% at 511 keV throughout most of the detector volume. Improved resolution is expected with properly shielded front-end electronics. Measurements made using a collimated beam established the efficacy of the steering electrodes in facilitating enhanced charge collection across anodes, as well as a spatial resolution of 0.44 ± 0.07 mm in the direction orthogonal to the electrode planes. Finally, measurements based on coincidence electronic collimation yielded a point spread function with 0.78 ± 0.10 mm FWHM, demonstrating 1 mm spatial resolution capability transverse to the anodes-as expected from the 1 mm anode pitch. These findings indicate that the CZT-based detector concept has excellent performance and shows great promise for a high-resolution PET system.

  15. A 3D Computational Study on the Air-Blast Atomization of a Planar Liquid Layer

    NASA Astrophysics Data System (ADS)

    Chiodi, Robert; Desjardins, Olivier

    2016-11-01

    The air-blast atomization of a planar liquid layer is a complex fluid phenomenon involving the destabilization of a low speed liquid layer by a high speed gas coflow. While progress has been made in recent years on understanding the instability of the liquid surface, it remains difficult to accurately predict using stability analysis and requires special expertise and equipment to perform thorough experiments. Simulations provide an excellent way to conduct parametric studies to determine the effect of splitter plate geometry and momentum flux ratio on the frequency and wavelengths of instability, however, they are extremely difficult due to the high density ratio and large range of length and time scales present in the flow. Using an accurate conservative level set method in conjunction with a newly reformulated reinitialization equation, we perform 3D simulations of the air-blast atomization of a planar liquid layer and compare them to experiments. We then go on to explore the role momentum flux ratio plays in the longitudinal and transverse wavelengths of instability.

  16. Study of a high-resolution, 3-D positioning cadmium zinc telluride detector for PET

    PubMed Central

    Gu, Y; Matteson, J L; Skelton, R T; Deal, A C; Stephan, E A; Duttweiler, F; Gasaway, T M; Levin, C S

    2011-01-01

    This paper investigates the performance of 1 mm resolution Cadmium Zinc Telluride (CZT) detectors for positron emission tomography (PET) capable of positioning the 3-D coordinates of individual 511 keV photon interactions. The detectors comprise 40 mm × 40 mm × 5 mm monolithic CZT crystals that employ a novel cross-strip readout with interspersed steering electrodes to obtain high spatial and energy resolution. The study found a single anode FWHM energy resolution of 3.06±0.39% at 511 keV throughout most the detector volume. Improved resolution is expected with properly shielded front-end electronics. Measurements made using a collimated beam established the efficacy of the steering electrodes in facilitating enhanced charge collection across anodes, as well as a spatial resolution of 0.44±0.07 mm in the direction orthogonal to the electrode planes. Finally, measurements based on coincidence electronic collimation yielded a point spread function with 0.78±0.10 mm FWHM, demonstrating 1 mm spatial resolution capability transverse to the anodes – as expected from the 1 mm anode pitch. These findings indicate that the CZT-based detector concept has excellent performance and shows great promise for a high-resolution PET system. PMID:21335649

  17. Experimental study of 3D Rayleigh-Taylor convection between miscible fluids in a porous medium

    NASA Astrophysics Data System (ADS)

    Nakanishi, Yuji; Hyodo, Akimitsu; Wang, Lei; Suekane, Tetsuya

    2016-11-01

    The natural convection of miscible fluids in porous media has applications in several fields, such as geoscience and geoengineering, and can be employed for the geological storage of CO2. In this study, we used X-ray computer tomography to visualize 3D fingering structures associated with the Rayleigh-Taylor instability between miscible fluids in a porous medium. In the early stages of the onset of the Rayleigh-Taylor instability, a fine crinkling pattern gradually appeared at the interface. As the wavelength and amplitude increased, descending fingers formed on the interface and extended vertically downward; in addition, ascending and highly symmetric fingers formed. The adjacent fingers were cylindrical in shape and coalesced to form large fingers. The fingers appearing on the interface tended to become finer with increasing Rayleigh number, which is consistent with linear perturbation theory. When the Péclet number exceeded 10, transverse dispersion increased the finger diameter and enhanced the finger coalescence, strongly impacting the decrease in finger number density. When mechanical dispersion was negligible, the finger-extension velocity and the dimensionless mass-transfer rate scaled with the characteristic velocity and the Rayleigh number with an appropriate length scale. Mechanical dispersion not only reduced the onset time but also enhanced the mass transport.

  18. 3D modeling of soil structure in urban groundwater areas: case studies in Kolpene, Rovaniemi, Finland

    NASA Astrophysics Data System (ADS)

    Kupila, Juho

    2015-04-01

    3D modeling of groundwater areas is an important research method in groundwater surveys. Model of geological soil structure improves the knowledge of linkage between land use planning and groundwater protection. Results can be used as base information when developing the water supply services and anticipating and performing the measures needed in case of environmental accidents. Also, collected information is utilized when creating the groundwater flow model. In Finland, structure studies have been conducted in cooperation (among others) with the municipalities and local water suppliers and with the authorities from the Centre for Economic Development, Transport and the Environment. Geological Survey of Finland carries out project "Structure studies in Kolpene groundwater area" in Rovaniemi, Finnish Lapland. Study site is located in northern Finland, in the vicinity of the city center of Rovaniemi. Extent of the area is about 13 square kilometers and there are lots of urban residential areas and other human activities. The objective of this project is to determine the geological structure of the Kolpene groundwater area so that the results can be used to estimate the validity of the present exclusion area and possible risks to the groundwater caused by the land use. Soil layers of the groundwater area are studied by means of collecting information by heavy drilling, geophysical surveying (ground penetrating radar and gravimeter measurements) and water sampling from the installed observation pipes. Also the general geological and hydrological mappings are carried out. Main results which will be produced are: 1) the model of the bedrock surface, 2) the model of the surface of the ground water and flow directions, 3) the thickness of ground water saturated soil layers and 4) location and main characteristics of the soil layers which are significant to the ground water conditions. The preparing studies have been started at the end of 2013 and the results will be

  19. Retrieval of cloud microphysical parameters from INSAT-3D: a feasibility study using radiative transfer simulations

    NASA Astrophysics Data System (ADS)

    Jinya, John; Bipasha, Paul S.

    2016-05-01

    Clouds strongly modulate the Earths energy balance and its atmosphere through their interaction with the solar and terrestrial radiation. They interact with radiation in various ways like scattering, emission and absorption. By observing these changes in radiation at different wavelength, cloud properties can be estimated. Cloud properties are of utmost importance in studying different weather and climate phenomena. At present, no satellite provides cloud microphysical parameters over the Indian region with high temporal resolution. INSAT-3D imager observations in 6 spectral channels from geostationary platform offer opportunity to study continuous cloud properties over Indian region. Visible (0.65 μm) and shortwave-infrared (1.67 μm) channel radiances can be used to retrieve cloud microphysical parameters such as cloud optical thickness (COT) and cloud effective radius (CER). In this paper, we have carried out a feasibility study with the objective of cloud microphysics retrieval. For this, an inter-comparison of 15 globally available radiative transfer models (RTM) were carried out with the aim of generating a Look-up- Table (LUT). SBDART model was chosen for the simulations. The sensitivity of each spectral channel to different cloud properties was investigated. The inputs to the RT model were configured over our study region (50°S - 50°N and 20°E - 130°E) and a large number of simulations were carried out using random input vectors to generate the LUT. The determination of cloud optical thickness and cloud effective radius from spectral reflectance measurements constitutes the inverse problem and is typically solved by comparing the measured reflectances with entries in LUT and searching for the combination of COT and CER that gives the best fit. The products are available on the website www.mosdac.gov.in

  20. Study on camera calibration technique of 3D color digitization system

    NASA Astrophysics Data System (ADS)

    Sun, Yuchen; Ge, Baozhen

    2006-11-01

    3D (three-dimensional) color digitization of an object is fulfilled by light-stripe method based on laser triangle principle and direct capturing method based on the color photo of the object. With this system, information matching between 3D and color sensor and data registration of different sensors are fulfilled by a sensor calibration process. The process uses the same round filament target to calibrate all of the sensors together. The principle and procedure of the process are presented in detail. Finally, a costume model is 3D color digitized and the obtaining data sets are processed by the method discussed, the results verify the correctness and feasibility of the algorithm.

  1. Investigations and improvements of digital holographic tomography applied for 3D studies of transmissive photonics microelements

    NASA Astrophysics Data System (ADS)

    Kujawinska, Malgorzata; Jozwicka, Agata; Kozacki, Tomasz

    2008-08-01

    In order to control performance of photonics microelements it is necessary to receive 3D information about their amplitude and phase distributions. To perform this task we propose to apply tomography based on projections gather by digital holography (DH). Specifically the DH capability to register several angular views of the object during a single hologram capture is employed, which may in future shorten significantly the measurement time or even allow for tomographic analysis of dynamic media. However such a new approach brings a lot of new issues to be considered. Therefore, in this paper the method limitations, with special emphasis on holographic reconstruction process, are investigated through extensive numerical experiments with special focus on 3D refractive index distribution determination.. The main errors and means of their elimination are presented. The possibility of 3D refractive index distribution determination by means of DHT is proved numerically and experimentally.

  2. HP-Lattice QSAR for dynein proteins: experimental proteomics (2D-electrophoresis, mass spectrometry) and theoretic study of a Leishmania infantum sequence.

    PubMed

    Dea-Ayuela, María Auxiliadora; Pérez-Castillo, Yunierkis; Meneses-Marcel, Alfredo; Ubeira, Florencio M; Bolas-Fernández, Francisco; Chou, Kuo-Chen; González-Díaz, Humberto

    2008-08-15

    The toxicity and inefficacy of actual organic drugs against Leishmaniosis justify research projects to find new molecular targets in Leishmania species including Leishmania infantum (L. infantum) and Leishmaniamajor (L. major), both important pathogens. In this sense, quantitative structure-activity relationship (QSAR) methods, which are very useful in Bioorganic and Medicinal Chemistry to discover small-sized drugs, may help to identify not only new drugs but also new drug targets, if we apply them to proteins. Dyneins are important proteins of these parasites governing fundamental processes such as cilia and flagella motion, nuclear migration, organization of the mitotic splinde, and chromosome separation during mitosis. However, despite the interest for them as potential drug targets, so far there has been no report whatsoever on dyneins with QSAR techniques. To the best of our knowledge, we report here the first QSAR for dynein proteins. We used as input the Spectral Moments of a Markov matrix associated to the HP-Lattice Network of the protein sequence. The data contain 411 protein sequences of different species selected by ClustalX to develop a QSAR that correctly discriminates on average between 92.75% and 92.51% of dyneins and other proteins in four different train and cross-validation datasets. We also report a combined experimental and theoretic study of a new dynein sequence in order to illustrate the utility of the model to search for potential drug targets with a practical example. First, we carried out a 2D-electrophoresis analysis of L. infantum biological samples. Next, we excised from 2D-E gels one spot of interest belonging to an unknown protein or protein fragment in the region M<20,200 and pI<4. We used MASCOT search engine to find proteins in the L. major data base with the highest similarity score to the MS of the protein isolated from L. infantum. We used the QSAR model to predict the new sequence as dynein with probability of 99.99% without

  3. A novel 3D integrated platform for the high-resolution study of cell migration plasticity.

    PubMed

    Schneider, Julian; Bachmann, Tobias; Franco, Davide; Richner, Patrizia; Galliker, Patrick; Tiwari, Manish K; Ferrari, Aldo; Poulikakos, Dimos

    2013-08-01

    Understanding the mechanisms of interstitial cancer migration is of great scientific and medical interest. Creating 3D platforms, conducive to optical microscopy and mimicking the physical parameters (in plane and out of plane) involved in interstitial migration, is a major step forward in this direction. Here, a novel approach is used to directly print free-form, 3D micropores on basal scaffolds containing microgratings optimized for contact guidance. The platforms so formed are validated by monitoring cancer cell migration and micropore penetration with high-resolution optical microscopy. The shapes, sizes and deformability of the micropores are controllable, paving the way to decipher their role in interstitial migration.

  4. A feasibility study of a 3-D finite element solution scheme for aeroengine duct acoustics

    NASA Technical Reports Server (NTRS)

    Abrahamson, A. L.

    1980-01-01

    The advantage from development of a 3-D model of aeroengine duct acoustics is the ability to analyze axial and circumferential liner segmentation simultaneously. The feasibility of a 3-D duct acoustics model was investigated using Galerkin or least squares element formulations combined with Gaussian elimination, successive over-relaxation, or conjugate gradient solution algorithms on conventional scalar computers and on a vector machine. A least squares element formulation combined with a conjugate gradient solver on a CDC Star vector computer initially appeared to have great promise, but severe difficulties were encountered with matrix ill-conditioning. These difficulties in conditioning rendered this technique impractical for realistic problems.

  5. 3D Numerical Study of Typical CME Event: The 2010-04-03 Event

    NASA Astrophysics Data System (ADS)

    Zhou, Y.; Feng, X. S.; Zhao, X.

    2014-12-01

    The coronal mass ejection (CME) event on April 3, 2010 is the first fast CME observed by STEREO SECCHI/HI for the full Sun-Earth line. Such an event provides us a good opportunity to study the propagation and evolution of CME from the Sun up to 1 AU. In this paper, we study the time-dependent evolution and propagation of this event from the Sun to Earth using the 3D SIP-CESE MHD model. The CME is initiated by a simple spherical plasmoid model: a spheromak magnetic structure with high speed, high pressure and high plasma density plasmoid. We find that the results can successfully reproduce the observations in the STEREO A/B COR1 and COR2 field of view and generate many basic structures of the in situ measurement: such as the similar curves of the plasma density and velocity, an increase in the magnetic field magnitude, the large-scale smooth magnetic field rotation and prolonged southward IMF (a well known source of magnetic storms). The MHD model gives the shock arrival time at Earth with an error of ˜ 1.5 hours. Finally, we analyze in detail the propagation velocity, the spread angle, the trajectory of CME. The speed of the CME rapidly increases from near the Sun, then decreases due to interaction with the solar wind ambient. The spread angle of the CME quickly increases due to lateral material expansion by the pressure gradients within the realistic solar wind background, then the expansion decreases with distance and ends until a pressure equilibrium is established. We also study the CME deflection and find that the CME almost does not deflects in the latitudinal and longitudinal direction during its propagation from the Sun to 1 AU.

  6. Studies of mixed HEU-LEU-MTR cores using 3D models

    SciTech Connect

    Haenggi, P.; Lehmann, E.; Hammer, J.; Christen, R.

    1997-08-01

    Several different core loadings were assembled at the SAPHIR research reactor in Switzerland combining the available types of MTR-type fuel elements, consisting mainly of both HEU and LEU fuel. Bearing in mind the well known problems which can occur in such configurations (especially power peaking), investigations have been carried out for each new loading with a 2D neutron transport code (BOXER). The axial effects were approximated by a global buckling value and therefore the radial effects could be studied in considerably detail. Some of the results were reported at earlier RERTR meetings and were compared to those obtained by other methods and with experimental values. For the explicit study of the third dimension of the core, another code (SILWER), which has been developed in PSI for LWR power plant cores, has been selected. With the help of an adapted model for the MTR-core of SAPHIR, several important questions have been addressed. Among other aspects, the estimation of the axial contribution to the hot channel factors, the influence of the control rod position and of the Xe-poisoning on the power distribution were studied. Special attention was given to a core position where a new element was assumed placed near a empty, water filled position. The comparison of elements of low and high enrichments at this position was made in terms of the induced power peaks, with explicit consideration of axial effects. The program SILWER has proven to be applicable to MTR-cores for the investigation of axial effects. For routine use as for the support of reactor operation, this 3D code is a good supplement to the standard 2D model.

  7. Study of a viewer tracking system with multiview 3D display

    NASA Astrophysics Data System (ADS)

    Yang, Jinn-Cherng; Wu, Chang-Shuo; Hsiao, Chuan-Heng; Yang, Ming-Chieh; Liu, Wen-Chieh; Hung, Yi-Ping

    2008-02-01

    An autostereoscopic display provides users great enjoyment of stereo visualization without uncomfortable and inconvenient drawbacks of wearing stereo glasses. However, bandwidth constraints of current multi-view 3D display severely restrict the number of views that can be simultaneously displayed without degrading resolution or increasing display cost unacceptably. An alternative to multiple view presentation is that the position of observer can be measured by using viewer-tracking sensor. It is a very important module of the viewer-tracking component for fluently rendering and accurately projecting the stereo video. In order to render stereo content with respect to user's view points and to optically project the content onto the left and right eyes of the user accurately, the real-time viewer tracking technique that allows the user to move around freely when watching the autostereoscopic display is developed in this study. It comprises the face detection by using multiple eigenspaces of various lighting conditions, fast block matching for tracking four motion parameters of the user's face region. The Edge Orientation Histogram (EOH) on Real AdaBoost to improve the performance of original AdaBoost algorithm is also applied in this study. The AdaBoost algorithm using Haar feature in OpenCV library developed by Intel to detect human face and enhance the accuracy performance with rotating image. The frame rate of viewer tracking process can achieve up to 15 Hz. Since performance of the viewer tracking autostereoscopic display is still influenced under variant environmental conditions, the accuracy, robustness and efficiency of the viewer-tracking system are evaluated in this study.

  8. New set of 2D/3D thermodynamic indices for proteins. A formalism based on “ Molten Globule” theory

    NASA Astrophysics Data System (ADS)

    Ruiz-Blanco Yasser, B.; García, Y.; Sotomayor-Torres, C. M.; Yovani, Marrero-Ponce

    We define eight new macromolecular indices, and several related descriptors for proteins. The coarse grained methodology used for its deduction ensures its fast execution and becomes a powerful potential tool to explore large databases of protein structures. The indices are intended for stability studies, predicting Φ-values, predicting folding rate constants, protein QSAR/QSPR as well as protein alignment studies. Also, these indices could be used as scoring function in protein-protein docking or 3D protein structure prediction algorithms and any others applications which need a numerical code for proteins and/or residues from 2D or 3D format.

  9. Molecular interaction study of flavonoid derivative 3d with human serum albumin using multispectroscopic and molecular modeling approach.

    PubMed

    Wei, Juntong; Jin, Feng; Wu, Qin; Jiang, Yuyang; Gao, Dan; Liu, Hongxia

    2014-08-01

    Human serum albumin (HSA) has been developed as a model protein to study drug-protein interaction. In the present work, the interaction between our synthesized flavonoid derivative 3d (possessing potent antitumor activity against HepG2 cells) and HSA was investigated using fluorescence spectroscopy, circular dichroism spectroscopy, UV-vis spectroscopy and molecular modeling approach. Fluorescence spectroscopy showed that the fluorescence of HSA can be quenched remarkably by 3d under physiological condition with a slight shift of maximum fluorescence emission bands from 360nm to 363nm. Calculated results from Stern-Volmer equation and modified Stern-Volmer equation indicated that the fluorescence was quenched by static quenching processing with association constant 5.26±0.04×10(4)L mol(-1) at 298K. After comprehensive consideration of the free energy change ΔG, enthalpy change ΔH and entropy change ΔS, electrostatic interactions were confirmed as the main factor that participate in stabilizing the 3d-HSA complex. Both dichroism spectroscopy and UV-vis spectroscopy indicated conformational change of HSA after binding to 3d. Moreover, the structure of HSA was loosened and the percentage of α-helix decreased with increasing concentration of 3d. Molecular modeling results demonstrated that 3d could bind to HSA well into subdomain IIA, which is related to its capability of deposition and delivery. Three cation-π interactions and three hydrogen bonds occurred between 3d and amino acid residuals ARG218, ARG222 and LYS199. In conclusion, flavonoid derivative 3d can bind to HSA with noncovalent bond in a relatively stable way, so it can be delivered by HSA in a circulatory system.

  10. A 3-D reconstruction solution to current density imaging based on acoustoelectric effect by deconvolution: a simulation study.

    PubMed

    Yang, Renhuan; Li, Xu; Song, Aiguo; He, Bin; Yan, Ruqiang

    2013-05-01

    Hybrid imaging modality combining ultrasound scanning and electrical current density imaging through the acoustoelectric (AE) effect may potentially provide solutions to imaging electrical activities and properties of biological tissues with high spatial resolution. In this study, a 3-D reconstruction solution to ultrasound current source density imaging (UCSDI) by means of Wiener deconvolution is proposed and evaluated through computer simulations. As compared to previous 2-D UCSDI problem, in a 3-D volume conductor with broadly distributed current density field, the AE signal becomes a 3-D</