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Sample records for 3d qsar analysis

  1. 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.

  2. 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.

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

    PubMed

    Santos-Filho, O A; Mishra, R 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.

  4. 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.

  5. 3D-QSAR Investigation of Synthetic Antioxidant Chromone Derivatives by Molecular Field Analysis

    PubMed Central

    Samee, Weerasak; Nunthanavanit, Patcharawee; Ungwitayatorn, Jiraporn

    2008-01-01

    A series of 7-hydroxy, 8-hydroxy and 7,8-dihydroxy synthetic chromone derivatives was evaluated for their DPPH free radical scavenging activities. A training set of 30 synthetic chromone derivatives was subject to three-dimensional quantitative structure-activity relationship (3D-QSAR) studies using molecular field analysis (MFA). The substitutional requirements for favorable antioxidant activity were investigated and a predictive model that could be used for the design of novel antioxidants was derived. Regression analysis was carried out using genetic partial least squares (G/PLS) method. A highly predictive and statistically significant model was generated. The predictive ability of the developed model was assessed using a test set of 5 compounds (r2pred = 0.924). The analyzed MFA model demonstrated a good fit, having r2 value of 0.868 and cross-validated coefficient r2cv value of 0.771. PMID:19325746

  6. 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

  7. 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.

  8. Definition of an uptake pharmacophore of the serotonin transporter through 3D-QSAR analysis.

    PubMed

    Pratuangdejkul, J; Schneider, B; Jaudon, P; Rosilio, V; Baudoin, E; Loric, S; Conti, M; Launay, J-M; Manivet, P

    2005-01-01

    The serotonergic system plays a critical role in a wide variety of physiological and behavioral processes. Dysregulation of the tightly controlled extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) appears to be at the origin of a host of metabolic and psychiatric disorders. Since the plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration, SERT is the target of most drugs interacting with the serotonergic system. Unfortunately, some of the drugs towards SERT (e.g. amphetamine derivatives) interfere with cell homeostasis leading to cell toxicity. Developing new SERT ligands devoid of any side-effect represents a major priority in the treatment of 5-HT-associated pathologies. Here, we report structure-activity relationships (SAR) and three-dimensional QSAR (3D-QSAR) studies of a library of 121 compounds including 5-HT analogs, harmanes, benzothiazoles, indanones, amphetamine derivatives and substrate-type 5-HT releasers, with the goal of identifying the structural determinants crucial for SERT uptake. In the absence of data about the bioactive form of 5-HT, conformational analysis of 5-HT was performed using quantum chemistry calculations. This led to three 5-HT stable conformers with anti, -gauche and +gauche side-chain conformation. These conformers, used as templates for superimposition with all the library compounds, enabled the design of a reliable 6-points pharmacophore representative of SERT uptake activity. Molecular dynamics (MD) simulations performed with compounds that are efficiently, moderately, poorly or not transported by SERT allowed to assess the validity of our pharmacophore. Altogether, our data provide for the first time a reliable pharmacophore of SERT uptake activity, which may help to the design of new drugs targeting SERT.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. Molecular field analysis and 3D-quantitative structure-activity relationship study (MFA 3D-QSAR) unveil novel features of bile acid recognition at TGR5.

    PubMed

    Macchiarulo, Antonio; Gioiello, Antimo; Thomas, Charles; Massarotti, Alberto; Nuti, Roberto; Rosatelli, Emiliano; Sabbatini, Paola; Schoonjans, Kristina; Auwerx, Johan; Pellicciari, Roberto

    2008-09-01

    Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.

  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. 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...

  17. 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...

  18. 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

  19. 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.

  20. 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.

  1. Binding of Matrix Metalloproteinase Inhibitors to Extracellular Matrix: 3D-QSAR Analysis

    PubMed Central

    Zhang, Yufen; Lukacova, Viera; Bartus, Vladimir; Nie, Xiaoping; Sun, Guorong; Manivannan, Ethirajan; Ghorpade, Sandeep R.; Jin, Xiaomin; Manyem, Shankar; Sibi, Mukund P.; Cook, Gregory R.; Balaz, Stefan

    2008-01-01

    Binding to the extracellular matrix (ECM), one of the most abundant human protein complexes, significantly affects drug disposition. Specifically, the interactions with ECM determine the free concentrations of small molecules acting in tissues, including signaling peptides, inhibitors of tissue remodeling enzymes such as matrix metalloproteinases (MMPs), and other drug candidates. The nature of ECM binding was elucidated for 63 MMP inhibitors, for which the association constants to an ECM mimic were reported here. The data did not correlate with lipophilicity as a common determinant of structure-nonspecific, orientation-averaged binding. A hypothetical structure of the binding site of the solidified ECM surrogate was analyzed using the Comparative Molecular Field Analysis (CoMFA), which needed to be applied in our multi-mode variant. This fact indicates that the compounds bind to ECM in multiple modes, which cannot be considered as completely orientation-averaged and exhibit structural dependence. The novel CoMFA models, exhibiting satisfactory descriptive and predictive abilities, are suitable for prediction of the ECM binding for the untested chemicals, which are within applicability domains. The results contribute to a better prediction of the pharmacokinetic parameters such as the distribution volume and the tissue-blood partition coefficients, in addition to a more imminent benefit for the development of more effective MMP inhibitors. PMID:18844670

  2. 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.

  3. 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.

  4. 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.

  5. Molecular modeling, quantum polarized ligand docking and structure-based 3D-QSAR analysis of the imidazole series as dual AT1 and ETA receptor antagonists

    PubMed Central

    Singh, Khuraijam Dhanachandra; Muthusamy, Karthikeyan

    2013-01-01

    Aim: Both endothelin ETA receptor antagonists and angiotensin AT1 receptor antagonists lower blood pressure in hypertensive patients. A dual AT1 and ETA receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT1 and ETA receptor antagonists. Methods: Molecular modeling approach combining quantum-polarized ligand docking (QPLD), MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT1 and ETA receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results: 3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship: substitution of methoxymethyl and cyclooctanone might increase the activity against AT1 receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ETA receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT1 receptor but significantly increased its activity against ETA receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ETA receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT1 and ETA receptor antagonists. Conclusion: This study may provide some insights into the development of novel potent dual ETA and AT1 receptor antagonists. As a result, five compounds are

  6. Analysis of B-Raf[Formula: see text] inhibitors using 2D and 3D-QSAR, molecular docking and pharmacophore studies.

    PubMed

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

    2015-11-01

    In the present work, a molecular modeling study was carried out using 2D and 3D quantitative structure-activity relationships for the various series of compounds known as B-Raf[Formula: see text] inhibitors. For 2D-QSAR analysis, a linear model was developed by MLR based on GA-OLS with appropriate results [Formula: see text], which was validated by several external validation techniques. To perform a 3D-QSAR analysis, CoMFA and CoMSIA methods were used. The selected CoMFA model could provide reliable statistical values [Formula: see text] based on the training set in the biases of the selected alignment. Using the same selected alignment, a statistically reliable CoMSIA model, out of thirty-one different combinations, was also obtained [Formula: see text]. The predictive accuracy of the derived models was rigorously evaluated with the external test set of nineteen compounds based on several validation techniques. Molecular docking simulations and pharmacophore analyses were also performed to derive the true conformations of the most potent inhibitors with B-Raf[Formula: see text] kinase.

  7. 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.

  8. 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.

  9. Novel N-(3-carboxyl-9-benzyl-beta-carboline-1-yl)ethylamino acids: synthesis, anti-tumor evaluation, intercalating determination, 3D QSAR analysis and docking investigation.

    PubMed

    Wu, Jianhui; Zhao, Ming; Qian, Keduo; Lee, Kuo-Hsiung; Morris-Natschke, Susan; Peng, Shiqi

    2009-10-01

    Sixteen novel N-(3-carboxyl-9-benzyl-beta-carboline-1-yl)ethylamino acids (6a-p) were synthesized as intercalating lead compounds. In the in vitro cytotoxic assay their IC(50) values against five human carcinoma cell lines ranged from 10.95 microM to about 400 microM. On S180 mouse model eight of them exhibited anti-tumor action, four of them showed the same anti-tumor potency as that of cytarabine. The preliminary toxicity evaluation revealed that the LD(50) values of 6a-p should be more than 500 mg/kg. With CT DNA as model system an intercalating mechanism was explored. Using 3D QSAR analysis the relationship of the in vivo anti-tumor activity and the structure was quantitatively described. By docking 6a-p onto d(CGATCG)(2) oligonucleotides the intercalation was demonstrated.

  10. 3D pharmacophore mapping using 4D QSAR analysis for the cytotoxicity of lamellarins against human hormone-dependent T47D breast cancer cells.

    PubMed

    Thipnate, Poonsiri; Liu, Jianzhong; Hannongbua, Supa; Hopfinger, A J

    2009-10-01

    4D quantitative structure-activity relationship (QSAR) and 3D pharmacophore models were built and investigated for cytotoxicity using a training set of 25 lamellarins against human hormone dependent T47D breast cancer cells. Receptor-independent (RI) 4D QSAR models were first constructed from the exploration of eight possible receptor-binding alignments for the entire training set. Since the training set is small (25 compounds), the generality of the 4D QSAR paradigm was then exploited to devise a strategy to maximize the extraction of binding information from the training set and to also permit virtual screening of diverse lamellarin chemistry. 4D QSAR models were sought for only six of the most potent lamellarins of the training set as well as another subset composed of lamellarins with constrained ranges in molecular weight and lipophilicity. This overall modeling strategy has permitted maximizing 3D pharmacophore information from this small set of structurally complex lamellarins that can be used to drive future analog synthesis and the selection of alternate scaffolds. Overall, it was found that the formation of an intermolecular hydrogen bond and the hydrophobic interactions for substituents on the E ring most modulate the cytotoxicity against T47D breast cancer cells. Hydrophobic substitutions on the F-ring can also enhance cytotoxic potency. A complementary high-throughput virtual screen to the 3D pharmacophore models, a 4D fingerprint QSAR model, was constructed using absolute molecular similarity. This 4D fingerprint virtual high-throughput screen permits a larger range of chemistry diversity to be assayed than with the 4D QSAR models. The optimized 4D QSAR 3D pharmacophore model has a leave-one-out cross-correlation value of xv-r2 = 0.947, while the optimized 4D fingerprint virtual screening model has a value of xv-r2 = 0.719. This work reveals that it is possible to develop significant QSAR, 3D pharmacophore, and virtual screening models for a small set

  11. 3D-Pharmacophore Mapping Using 4D-QSAR Analysis for the Cytotoxicity of Lamellarins Against Human Hormone-Dependent T47D Breast Cancer Cells

    PubMed Central

    Thipnate, Poonsiri; Liu, Jianzhong; Hannongbua, Supa; Hopfinger, A. J.

    2009-01-01

    4D-QSAR and 3D-pharmacophore models were built and investigated for the cytotoxicity using a training set of 25 lamellarins against human hormone dependent T47D breast cancer cells. Receptor-independent (RI) 4D-QSAR models were first constructed from the exploration of eight possible receptor binding alignments for the entire training set. Since the training set is small (25 compounds), the generality of the 4D-QSAR paradigm was then exploited to devise a strategy to maximize the extraction of binding information from the training set, and to also permit virtual screening of diverse lamellarin chemistry. 4D-QSAR models were sought for only six of the most potent lamellarins of the training set as well as another subset composed of lamellarins with constrained ranges in molecular weight and lipophilicty. This overall modeling strategy has permitted maximizing 3D-pharmacophore information from this small set of structurally complex lamellarins that can be used to drive future analog synthesis and the selection of alternate scaffolds. Overall, it was found that formation of an intermolecular hydrogen bond and hydrophobic interactions for substituents on the E ring most modulate the cytotoxicity against T47D breast cancer cells. Hydrophobic substitutions on the F-ring can also enhance cytotoxic potency. A complementary high throughput virtual screen to the 3D-pharmacophore models, a 4D-fingerprint QSAR model, was constructed using absolute molecular similarity. This 4D-fingerprint virtual high throughput screen permits a larger range of chemistry diversity to be assayed than the 4D-QSAR models. The optimized 4D-QSAR 3D-pharmacophore model has a LOO cross-correlation value of xv-r2 = 0.947, while the optimized 4D-fingerprint virtual screening model has a value of xv-r2 = 0.719. This work reveals that it is possible to develop significant QSAR, 3D-pharmacophore and virtual screening models for a small set of lamellarins showing cytotoxic behavior in breast cancer screens

  12. 2D-QSAR and 3D-QSAR Analyses for EGFR Inhibitors

    PubMed Central

    Zhao, Manman; Zheng, Linfeng; Qiu, Chun

    2017-01-01

    Epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this study, EGFR inhibitors were investigated to build a two-dimensional quantitative structure-activity relationship (2D-QSAR) model and a three-dimensional quantitative structure-activity relationship (3D-QSAR) model. In the 2D-QSAR model, the support vector machine (SVM) classifier combined with the feature selection method was applied to predict whether a compound was an EGFR inhibitor. As a result, the prediction accuracy of the 2D-QSAR model was 98.99% by using tenfold cross-validation test and 97.67% by using independent set test. Then, in the 3D-QSAR model, the model with q2 = 0.565 (cross-validated correlation coefficient) and r2 = 0.888 (non-cross-validated correlation coefficient) was built to predict the activity of EGFR inhibitors. The mean absolute error (MAE) of the training set and test set was 0.308 log units and 0.526 log units, respectively. In addition, molecular docking was also employed to investigate the interaction between EGFR inhibitors and EGFR. PMID:28630865

  13. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. 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

  15. Probability issues in molecular design: predictive and modeling ability in 3D-QSAR schemes.

    PubMed

    Polanski, Jaroslaw; Gieleciak, Rafal; Bak, Andrzej

    2004-12-01

    In the current work we investigated 3D-QSAR data by the use of the coupled leave-several-out (LSO) and leave-one-out (LOO) cross-validation (CV) procedures. We verified the above mentioned scheme using both simulated data and real 3D QSAR data describing a series of CoMFA steroids, heterocyclic azo dyes and styrylquinoline HIV integrase inhibitors. Unlike in standard analyses, this technique characterizes individual method not by a single performance metrics but screens a whole possible modeling space by sampling different molecules into the training and test sets, respectively. This allowed us for the discussion of the information included in the estimators validating cross-validation procedures, as well as the comparison of the efficiency of several 3D QSAR schemes, in particular, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Surface Analysis (CoMSA). Moreover, it allows one to acquire some general knowledge about predictive and modeling ability in 3D QSAR method.

  16. Receptor Guided 3D-QSAR: A Useful Approach for Designing of IGF-1R Inhibitors

    PubMed Central

    Muddassar, M.; Pasha, F. A.; Chung, H. W.; Yoo, K. H.; Oh, C. H.; Cho, S. J.

    2008-01-01

    Research by other investigators has established that insulin-like growth factor‐1 receptor (IGF-1R) is a key oncological target, and that derivatives of 1, 3-disubstituted-imidazo[1,5-α] pyrazine are potent IGF-1R inhibitors. In this paper, we report on our three-dimensional quantitative structure activity relationship (3D-QSAR) studies for this series of compounds. We validated the 3D-QSAR models by the comparison of two major alignment schemes, namely, ligand-based (LB) and receptor-guided (RG) alignment schemes. The latter scheme yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (q2 = 0.35, r2 = 0.95) and comparative molecular similarity indices analysis (CoMSIA) (q2 = 0.51, r2 = 0.86). We submit that this might arise from the more accurate inhibitor alignment that results from using the structural information of the active site. We conclude that the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors, as well as to understand their binding affinity with the receptor. PMID:18385815

  17. Receptor guided 3D-QSAR: a useful approach for designing of IGF-1R inhibitors.

    PubMed

    Muddassar, M; Pasha, F A; Chung, H W; Yoo, K H; Oh, C H; Cho, S J

    2008-01-01

    Research by other investigators has established that insulin-like growth factor-1 receptor (IGF-1R) is a key oncological target, and that derivatives of 1, 3-disubstituted-imidazo[1,5-alpha] pyrazine are potent IGF-1R inhibitors. In this paper, we report on our three-dimensional quantitative structure activity relationship (3D-QSAR) studies for this series of compounds. We validated the 3D-QSAR models by the comparison of two major alignment schemes, namely, ligand-based (LB) and receptor-guided (RG) alignment schemes. The latter scheme yielded better 3D-QSAR models for both comparative molecular field analysis (CoMFA) (q(2) = 0.35, r(2) = 0.95) and comparative molecular similarity indices analysis (CoMSIA) (q(2) = 0.51, r(2) = 0.86). We submit that this might arise from the more accurate inhibitor alignment that results from using the structural information of the active site. We conclude that the receptor-guided 3D-QSAR may be helpful to design more potent IGF-1R inhibitors, as well as to understand their binding affinity with the receptor.

  18. 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

  19. 3d QSAR studies on a series of quinazoline derrivatives as tyrosine kinase (egfr) inhibitor: the k-nearest neighbor molecular field analysis approach.

    PubMed

    Noolvi, Malleshappa N; Patel, Harun M

    2010-06-01

    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 r(2) (q(2)) of 0.846, r(2) for external test set (pred_r2) 0.8029, coefficient of correlation of predicted data set (pred_r(2)se) 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.

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

    PubMed

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

    2005-11-01

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

  1. 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.

  2. 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.

  3. 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.

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

    PubMed

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

    2017-08-23

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

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 2D and 3D-QSAR studies on antiproliferative thiazolidine analogs

    NASA Astrophysics Data System (ADS)

    Liao, Si Yan; Qian, Li; Chen, Jin Can; Lu, Hai Liang; Zheng, Kang Cheng

    Two-dimensional (2D) and three-dimensional (3D) quantitative structure-activity relationships (QSARs) of 22 thiazolidine analogs with antiproliferative activity expressed as pIC50, which is defined as the negative value of the logarithm of necessary molar concentration of these compounds to cause 50% growth inhibition against melanoma cell lines WM-164, have been studied by using a combined method of the DFT, MM2 and statistics for 2D, as well as the comparative molecular field analysis (CoMFA) method for 3D. The established 2D-QSAR model in training set comprised of random 18 compounds shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient (R2A = 0.832) and the square of the cross-validation coefficient (q2 = 0.803). The same model was further applied to predict pIC50 values of the four compounds in the test set, and the resulting R2pred reaching 0.784, further confirms that this 2D-QSAR model has high predictive ability. The 3D-QSAR model also shows good correlative and predictive capabilities in terms of R2 (0.956) and q2 (0.615) obtained from CoMFA model. Further, the robustness of the CoMFA model was verified by bootstrapping analysis (100 runs) with R2bs (0.979) and SDbs (0.056). It is very interesting to find that the results from 2D- and 3D-QSAR analyses accord with each other, and they all show that the steric interaction plays a crucial role in determining the cytotoxicities of the compounds, and that selecting a moderate-size or appropriate-hydrophobicity substituent R as well as increasing the negative charges of C4 on phenyl ring at the same time are advantageous to improving the cytotoxicity. Such results can offer some useful theoretical references for directing the molecular design and understanding the action mechanism of this kind of compound with antiproliferative activity.

  12. 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.

  13. 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...

  14. 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...

  15. 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.

  16. 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.

  17. 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.

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

    PubMed

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

    2012-08-01

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

  19. 3D-QSAR studies on triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors.

    PubMed

    Shah, P; Siddiqi, M I

    2010-07-01

    3D-QSAR studies were carried out on a training set of 53 structurally highly diverse analogues of triclosan to investigate the correlation of the structural properties of triclosan derivatives with the inhibition of the activity of enoyl acyl carrier protein reductase in Plasmodium falciparum (PfENR) by employing Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). The crystal structure bound conformation of triclosan, was used as a template for aligning molecules. The probable binding mode conformations of other inhibitors were explored according to molecular docking and molecular mechanics poisson-boltzmann surface area (MM/PBSA) solvation free energy estimation methods using grid based linear Poisson-Boltzmann calculations. Predictive 3D-QSAR models, established using routine database alignment rule based on crystallographic-bound conformation of template molecule, produced statistically significant results with cross-validated r2 cv values of 0.64 and 0.54 and non-cross-validated r2 ncv values of 0.96 and 0.97 for CoMFA and CoMSIA models, respectively. The statistically significant models were validated by a test set of nine compounds with predictive r(2) values of 0.534 and 0.765 for CoMFA and CoMSIA respectively. Our QSAR model is able to successfully explain the geometric and electrostatic complementarities between ligands and receptor and provides useful guidelines to design novel triclosan derivatives as Plasmodium falciparum enoyl acyl carrier reductase inhibitors.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as alternative attractive tool to generate ligand-based 3D-QSARs.

    PubMed

    Moro, Stefano; Bacilieri, Magdalena; Ferrari, Cristina; Spalluto, Giampiero

    2005-03-01

    A database of 106 human A3 adenosine receptor antagonists was used to derive two alternative PLS models: one starting from CoMFA descriptors and the other starting from the autocorrelation descriptors. The peculiarity of this work is the introduction of autocorrelation vectors as molecular descriptors for the PLS analysis. The autocorrelation allows comparing molecules (and their properties) with different structures and with different spatial orientation without any previous alignment. In particular, Molecular Electrostatic Potential (MEP) was the property computed and its information encoded in autocorrelation vectors. The 3D spatial distribution and the values of the electrostatic potential is in fact largely responsible for the binding of a substrate to its receptor binding site. Validation was done with an external test set and the results of the two models were compared. Interestingly, our preliminary results seem to indicate that this new alternative approach could robustly compete with the already well consolidated CoMFA approach. In particular, we have suggested that it could be a very interesting tool to filter large structural database in several virtual screening applications.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 3D-QSAR and molecular fragment replacement study on diaminopyrimidine and pyrrolotriazine ALK inhibitors

    NASA Astrophysics Data System (ADS)

    Ke, Zhipeng; Lu, Tao; Liu, Haichun; Yuan, Haoliang; Ran, Ting; Zhang, Yanmin; Yao, Sihui; Xiong, Xiao; Xu, Jinxing; Xu, Anyang; Chen, Yadong

    2014-06-01

    Over expression of anaplastic lymphoma kinase (ALK) has been found in many types of cancer, and ALK is a promising therapeutic target for the treatment of cancer. To obtain new potent inhibitors of ALK, we conducted lead optimization using 3D-QSAR modeling and molecular docking investigation of 2,4-diaminopyrimidines and 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine-based compounds. Three favorable 3D-QSAR models (CoMFA with q2, 0.555; r2, 0.939; CoMSIA with q2, 0.625; r2, 0.974; Topomer CoMFA with q2, 0.557; r2 0.756) have been developed to predict the biological activity of novel compounds. Topomer Search was utilized for virtual screening to obtain suitable fragments. The novel compounds generated by molecular fragment replacement (MFR) were evaluated by Topomer CoMFA prediction, Glide (docking) and further evaluated with CoMFA and CoMSIA prediction. 25 novel 2,7-disubstituted-pyrrolo[2,1-f][1,2,4]triazine derivatives as potential ALK inhibitors were finally obtained. In this paper, a combination of CoMFA, CoMSIA and Topomer CoMFA could obtain favorable 3D-QSAR models and suitable fragments for ALK inhibitors optimization. The work flow which comprised 3D-QSAR modeling, Topomer Search, MFR, molecular docking and evaluating criteria could be applied to de novo drug design and the resulted compounds initiate us to further optimize and design new potential ALK inhibitors.

  14. 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.

  15. 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.

  16. 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.

  17. Multiple receptor conformation docking, dock pose clustering and 3D QSAR studies on human poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.

    PubMed

    Fatima, Sabiha; Jatavath, Mohan Babu; Bathini, Raju; Sivan, Sree Kanth; Manga, Vijjulatha

    2014-10-01

    Poly(ADP-ribose) polymerase-1 (PARP-1) functions as a DNA damage sensor and signaling molecule. It plays a vital role in the repair of DNA strand breaks induced by radiation and chemotherapeutic drugs; inhibitors of this enzyme have the potential to improve cancer chemotherapy or radiotherapy. Three-dimensional quantitative structure activity relationship (3D QSAR) models were developed using comparative molecular field analysis, comparative molecular similarity indices analysis and docking studies. A set of 88 molecules were docked into the active site of six X-ray crystal structures of poly(ADP-ribose)polymerase-1 (PARP-1), by a procedure called multiple receptor conformation docking (MRCD), in order to improve the 3D QSAR models through the analysis of binding conformations. The docked poses were clustered to obtain the best receptor binding conformation. These dock poses from clustering were used for 3D QSAR analysis. Based on MRCD and QSAR information, some key features have been identified that explain the observed variance in the activity. Two receptor-based QSAR models were generated; these models showed good internal and external statistical reliability that is evident from the [Formula: see text], [Formula: see text] and [Formula: see text]. The identified key features enabled us to design new PARP-1 inhibitors.

  18. 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.

  19. BCL::EMAS — Enantioselective Molecular Asymmetry Descriptor for 3D-QSAR

    PubMed Central

    Sliwoski, Gregory; Lowe, Edward W.; Butkiewicz, Mariusz; Meiler, Jens

    2013-01-01

    Stereochemistry is an important determinant of a molecule's biological activity. Stereoisomers can have different degrees of efficacy or even opposing effects when interacting with a target protein. Stereochemistry is a molecular property difficult to represent in 2D-QSAR as it is an inherently three-dimensional phenomenon. A major drawback of most proposed descriptors for 3D-QSAR that encode stereochemistry is that they require a heuristic for defining all stereocenters and rank-ordering its substituents. Here we propose a novel 3D-QSAR descriptor termed Enantioselective Molecular ASymmetry (EMAS) that is capable of distinguishing between enantiomers in the absence of such heuristics. The descriptor aims to measure the deviation from an overall symmetric shape of the molecule. A radial-distribution function (RDF) determines a signed volume of tetrahedrons of all triplets of atoms and the molecule center. The descriptor can be enriched with atom-centric properties such as partial charge. This descriptor showed good predictability when tested with a dataset of thirty-one steroids commonly used to benchmark stereochemistry descriptors (r2 = 0.89, q2 = 0.78). Additionally, EMAS improved enrichment of 4.38 versus 3.94 without EMAS in a simulated virtual high-throughput screening (vHTS) for inhibitors and substrates of cytochrome P450 (PUBCHEM AID891). PMID:22907158

  20. 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.

  1. 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.

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

    PubMed Central

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

    2015-01-01

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

  3. 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.

  4. 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.

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

    USDA-ARS?s Scientific Manuscript database

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

  6. 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.

  7. 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

  8. 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.

  9. Rigorous Treatment of Multi-species Multi-mode Ligand-Receptor Interactions in 3D-QSAR: CoMFA Analysis of Thyroxine Analogs Binding to Transthyretin

    PubMed Central

    Natesan, Senthil; Wang, Tiansheng; Lukacova, Viera; Bartus, Vladimir; Khandelwal, Akash; Balaz, Stefan

    2011-01-01

    For a rigorous analysis of the receptor-ligand binding, speciation of the ligands caused by ionization, tautomerism, covalent hydration, and dynamic stereoisomerism needs to be considered. Each species may bind in several orientations or conformations (modes), especially for flexible ligands and receptors. A thermodynamic description of the multi-species (MS), multi-mode (MM) binding events shows that the overall association constant is equal to the weighted sum of the sums of microscopic association constants of individual modes for each species, with the weights given by the unbound fractions of individual species. This expression is a prerequisite for a precise quantitative characterization of the ligand-receptor interactions in both structure-based and ligand-based structure-activity analyses. We have implemented the MS-MM correlation expression into the Comparative Molecular Field Analysis (CoMFA), which deduces a map of the binding site from structures and binding affinities of a ligand set, in the absence of experimental structural information on the receptor. The MS-MM CoMFA approach was applied to published data for binding to transthyretin of 28 thyroxine analogs, each forming up to four ionization species under physiological conditions. The published X-ray structures of several analogs, exhibiting multiple binding modes, served as templates for the MS-MM superposition of thyroxine analogs. Additional modes were generated for compounds with flexible alkyl substituents, to identify bound conformations. The results demonstrate that the MS-MM modification improved predictive abilities of the CoMFA models, even for the standard procedure with MS-MM selected species and modes. The predicted prevalences of individual modes and the generated receptor site model are in reasonable agreement with the available X-ray data. The calibrated model can help in the design of inhibitors of transthyretin amyloid fibril formation. PMID:21476521

  10. Recent Advances in Fragment-Based QSAR and Multi-Dimensional QSAR Methods

    PubMed Central

    Myint, Kyaw Zeyar; Xie, Xiang-Qun

    2010-01-01

    This paper provides an overview of recently developed two dimensional (2D) fragment-based QSAR methods as well as other multi-dimensional approaches. In particular, we present recent fragment-based QSAR methods such as fragment-similarity-based QSAR (FS-QSAR), fragment-based QSAR (FB-QSAR), Hologram QSAR (HQSAR), and top priority fragment QSAR in addition to 3D- and nD-QSAR methods such as comparative molecular field analysis (CoMFA), comparative molecular similarity analysis (CoMSIA), Topomer CoMFA, self-organizing molecular field analysis (SOMFA), comparative molecular moment analysis (COMMA), autocorrelation of molecular surfaces properties (AMSP), weighted holistic invariant molecular (WHIM) descriptor-based QSAR (WHIM), grid-independent descriptors (GRIND)-based QSAR, 4D-QSAR, 5D-QSAR and 6D-QSAR methods. PMID:21152304

  11. 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.

  12. 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.

  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. 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

  15. The 3D-QSAR study of antitumor arylsulfonylimidazolidinone derivatives by CoMFA and CoMSIA.

    PubMed

    Choo, Hea-Young Park; Choi, Suyoung; Jung, Sang-Hun; Koh, Hun Yeong; Pae, Ae Nim

    2003-10-15

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies for a series of arylsulfonylimidazolidinone derivatives having antitumor activity were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro cytotoxicity against human lung carcinoma (A549) exhibited a strong correlation with steric and electrostatic factors of the molecules. Four different types of models have been built using CoMFA and CoMSIA method with AM1 charge or Gasteiger-Huckel charge. By comparison of the statistical results of these models, model I obtained by CoMFA study with AM1 showed the best predictability of the antitumor activities based on the cross-validated value (0.642), conventional r2 (0.981), standard error of estimate (0.106) and PRESS value (0.170).

  16. Biological Evaluation and 3D-QSAR Studies of Curcumin Analogues as Aldehyde Dehydrogenase 1 Inhibitors

    PubMed Central

    Wang, Hui; Du, Zhiyun; Zhang, Changyuan; Tang, Zhikai; He, Yan; Zhang, Qiuyan; Zhao, Jun; Zheng, Xi

    2014-01-01

    Aldehyde dehydrogenase 1 (ALDH1) is reported as a biomarker for identifying some cancer stem cells, and down-regulation or inhibition of the enzyme can be effective in anti-drug resistance and a potent therapeutic for some tumours. In this paper, the inhibitory activity, mechanism mode, molecular docking and 3D-QSAR (three-dimensional quantitative structure activity relationship) of curcumin analogues (CAs) against ALDH1 were studied. Results demonstrated that curcumin and CAs possessed potent inhibitory activity against ALDH1, and the CAs compound with ortho di-hydroxyl groups showed the most potent inhibitory activity. This study indicates that CAs may represent a new class of ALDH1 inhibitor. PMID:24840575

  17. 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.

  18. 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.

  19. 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

  20. 3D descriptors calculation and conformational search to investigate potential bioactive conformations, with application in 3D-QSAR and virtual screening in drug design.

    PubMed

    da Silva, Carlos Henrique Tomich de Paula; Taft, Carlton Anthony

    2017-10-01

    The knowledge of the bioactive conformation for an active hit is relevant because of the easier interpretation and the general quality of the recognition models of protein and ligand. With the aim of investigating potential bioactive conformations without previous structural knowledge of the molecular target, we present herewith a 'protocol' that could be used which includes generation of low-energy conformations, calculations of tridimensional descriptors and investigation of structural similarity via principal component analysis. The protocol was used in the search for potential bioactive conformations. An initial selection of targets was made from a set of protein-ligand complexes with structure deposited in the Protein Data Bank, which was systematically filtered by lead-like rules, resulting in 45 ligands of 8 important therapeutic targets. After extensive optimization of the protocol and parameters of both OMEGA and Pentacle softwares, the best results were obtained for series of compounds such as the beta-trypsin and urokinase inhibitors, which are more structurally related among each other, inside the respective therapeutic class. Future improvements of the protocol, including a suitable choice and combination of robust 3D descriptors, could yield more reliable and less restrictive results, with general and diverse applications in drug design, in particular for improving the 3D-QSAR methodologies as well as virtual screening experiments for a more reliable selection of new lead compounds for different molecular targets.

  1. Combined 3D-QSAR modeling and molecular docking study on multi-acting quinazoline derivatives as HER2 kinase inhibitors.

    PubMed

    Mirzaie, Sako; Monajjemi, Majid; Hakhamaneshi, Mohammad Saeed; Fathi, Fardin; Jamalan, Mostafa

    2013-01-01

    A series of new quinazoline derivatives has been recently reported as potent multi-acting histone deacetylase (HDAC), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER2) inhibitors. HER2 is one of the major targets for the treatment of breast cancer and other carcinomas. Three-dimensional structure-activity relationship (3D-QSAR) is a well-known technique, which is used to drug design and development. This technique is used for quantitatively predicting the interaction between a molecule and the active site of a specific target. For each 3D-QSAR study, a three-dimensional model is created from a large curve fit to find a fitting between computational descriptors and biological activity. This model could be used as a predictive tool in drug design. The best model has the highest correlation between theoretical and experimental data. Self-Organizing Molecular Field Analysis (SOMFA), a grid-based and alignment-dependent 3D-QSAR method, is employed to study the correlation between the molecular properties and HER2 inhibitory potency of the quinazoline derivatives. Before presentation of inhibitor structures to SOMFA study, conformation of inhibitors was determined by AutoDock4, HyperChem and AutoDock Vina, separately. Overall, six independent models were produced and evaluated by the statistical partial least square (PLS) analysis. Among the several generated 3D-QSARs, the best model was selected on the basis of its statistical significance and predictive potential. The model derived from the superposition of docked conformation with AutoDock Vina with reasonable cross-validated q(2) (0.767), non cross-validated r(2) (0.815) and F-test (97.22) values showed a desirable predictive capability. Analysis of SOMFA model could provide some useful information in the design of novel HER2 kinase inhibitors with better spectrum of activity.

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

    PubMed

    Sivan, Sree Kanth; Manga, Vijjulatha

    2010-06-01

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

  3. Molecular docking and 3D QSAR studies on 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes based on the structural modeling of human CCR5 receptor.

    PubMed

    Xu, Yong; Liu, Hong; Niu, Chunying; Luo, Cheng; Luo, Xiaomin; Shen, Jianhua; Chen, Kaixian; Jiang, Hualiang

    2004-12-01

    In the present study, we have used an approach combining protein structure modeling, molecular dynamics (MD) simulation, automated docking, and 3D QSAR analyses to investigate the detailed interactions of CCR5 with their antagonists. Homology modeling and MD simulation were used to build the 3D model of CCR5 receptor based on the high-resolution X-ray structure of bovine rhodopsin. A series of 64 CCR5 antagonists, 1-amino-2-phenyl-4-(piperidin-1-yl)-butanes, were docked into the putative binding site of the 3D model of CCR5 using the docking method, and the probable interaction model between CCR5 and the antagonists were obtained. The predicted binding affinities of the antagonists to CCR5 correlate well with the antagonist activities, and the interaction model could be used to explain many mutagenesis results. All these indicate that the 3D model of antagonist-CCR5 interaction is reliable. Based on the binding conformations and their alignment inside the binding pocket of CCR5, three-dimensional structure-activity relationship (3D QSAR) analyses were performed on these antagonists using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Both CoMFA and CoMSIA provide statistically valid models with good correlation and predictive power. The q(2)(r(cross)(2)) values are 0.568 and 0.587 for CoMFA and CoMSIA, respectively. The predictive ability of these models was validated by six compounds that were not included in the training set. Mapping these models back to the topology of the active site of CCR5 leads to a better understanding of antagonist-CCR5 interaction. These results suggest that the 3D model of CCR5 can be used in structure-based drug design and the 3D QSAR models provide clear guidelines and accurate activity predictions for novel antagonist design.

  4. 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.

  5. 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. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. 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.

  7. 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

  8. 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.

  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. 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. 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.

  12. 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.

  13. 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.

  14. 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.

  15. A new computer program for QSAR-analysis: ARTE-QSAR.

    PubMed

    Van Damme, Sofie; Bultinck, Patrick

    2007-08-01

    A new computer program has been designed to build and analyze quantitative-structure activity relationship (QSAR) models through regression analysis. The user is provided with a range of regression and validation techniques. The emphasis of the program lies mainly in the validation of QSAR models in chemical applications. ARTE-QSAR produces an easy interpretable output from which the user can conclude if the obtained model is suitable for prediction and analysis.

  16. 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.

  17. 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.

  18. Sensitivity Analysis of QSAR Models for Assessing Novel Military Compounds

    DTIC Science & Technology

    2009-01-01

    erties, such as log P, would aid in estimating a chemical’s environmental fate and toxicology when applied to QSAR modeling. Granted, QSAR mod- els, such...ER D C TR -0 9 -3 Strategic Environmental Research and Development Program Sensitivity Analysis of QSAR Models for Assessing Novel...Environmental Research and Development Program ERDC TR-09-3 January 2009 Sensitivity Analysis of QSAR Models for Assessing Novel Military Compound

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. Insights into phenylalanine derivatives recognition of VLA-4 integrin: from a pharmacophoric study to 3D-QSAR and molecular docking analyses.

    PubMed

    Macchiarulo, Antonio; Costantino, Gabriele; Meniconi, Mirco; Pleban, Karin; Ecker, Gerhard; Bellocchi, Daniele; Pellicciari, Roberto

    2004-01-01

    The very late antigen-4 (VLA-4), also known as integrin alpha4beta1, is expressed on monocytes, T- and B-lympohocytes, basophils, and eosinophils and is involved in the massive recruitment of granulocytes in different pathological conditions such as multiple sclerosis and asthma. VLA-4 interacts with its endogenous ligand VCAM-1 during chronic inflammation, and blockade of VLA-4 /VCAM-1 interaction is a potential target for immunosuppression. Two classes of VLA-4 antagonists have so far been reported: beta-amino acid derivatives containing a diaryl urea moiety (BIO-1211) and phenylalanine derivatives (TR-14035). With the aim of clarifying the structural basis responsible for VLA-4 recognition by phenylalanine derivatives, we developed a combined computational study on a set of 128 antagonists available through the literature. Our computational approach is composed of three parts. (i) A VCAM-1 based pharmacophore was constructed with a restricted number of phenylalanine derivatives to identify the region of the protein that resembles synthetic antagonists. The pharmacophore was instrumental in constructing an alignment of a set of 128 compounds. This alignment was exploited to build a pseudoreceptor model with the RECEPTOR program. (ii) 3D-QSAR analysis was carried out on the computed electrostatic and steric interaction energies with the pseudoreceptor surface. The 3D-QSAR analysis yielded a predictive model able to explain much of the variance of the 128 antagonists. (iii) A homology modeling study of the headpiece of VLA-4 based on the crystal structure of alphavbeta3 was performed. Docking experiments of TR-14035 into the binding site of VLA-4 aided the interpretation of the 3D-QSAR model. The obtained results will be fruitful for the design of new potent and selective antagonists of VLA-4. Copyright 2004 American Chemical Society

  4. 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.

  5. 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. Copyright © 2013 Elsevier Masson SAS. All

  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. In silico screening for identification of novel β-1,3-glucan synthase inhibitors using pharmacophore and 3D-QSAR methodologies.

    PubMed

    Meetei, Potshangbam Angamba; Rathore, R S; Prabhu, N Prakash; Vindal, Vaibhav

    2016-01-01

    The enzyme β-1,3-glucan synthase, which catalyzes the synthesis of β-1,3-glucan, an essential and unique structural component of the fungal cell wall, has been considered as a promising target for the development of less toxic anti-fungal agents. In this study, a robust pharmacophore model was developed and structure activity relationship analysis of 42 pyridazinone derivatives as β-1,3-glucan synthase inhibitors were carried out. A five-point pharmacophore model, consisting of two aromatic rings (R) and three hydrogen bond acceptors (A) was generated. Pharmacophore based 3D-QSAR model was developed for the same reported data sets. The generated 3D-QSAR model yielded a significant correlation coefficient value (R (2) = 0.954) along with good predictive power confirmed by the high value of cross-validated correlation coefficient (Q (2) = 0.827). Further, the pharmacophore model was employed as a 3D search query to screen small molecules database retrieved from ZINC to select new scaffolds. Finally, ADME studies revealed the pharmacokinetic efficiency of these compounds.

  8. 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.

  9. 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.

  10. 3D-QSAR, molecular docking, and molecular dynamic simulations for prediction of new Hsp90 inhibitors based on isoxazole scaffold.

    PubMed

    Abbasi, Maryam; Sadeghi-Aliabadi, Hojjat; Amanlou, Massoud

    2017-05-24

    Heat shock protein 90(Hsp90), as a molecular chaperone, play a crucial role in folding and proper function of many proteins. Hsp90 inhibitors containing isoxazole scaffold are currently being used in the treatment of cancer as tumor suppressers. Here in the present studies, new compounds based on isoxazole scaffold were predicted using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamic (MD) simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were also done. The steric and electrostatic contour map of CoMFA and CoMSIA were created. Hydrophobic, hydrogen bond donor and acceptor of CoMSIA model also were generated, and new compounds were predicted by CoMFA and CoMSIA contour maps. To investigate the binding modes of the predicted compounds in the active site of Hsp90, a molecular docking simulation was carried out. MD simulations were also conducted to evaluate the obtained results on the best predicted compound and the best reported Hsp90 inhibitors in the 3D-QSAR model. Findings indicate that the predicted ligands were stable in the active site of Hsp90.

  11. 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.

  12. Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

    PubMed Central

    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 r2cv values of 0.726 and 0.566, and r2 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. PMID:21673910

  13. 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

  14. 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

  15. Docking Based 3D-QSAR Study of Tricyclic Guanidine Analogues of Batzelladine K as anti-malarial agents

    NASA Astrophysics Data System (ADS)

    Ahmed, Nafees; Anwar, Sirajudheen; Thet Htar, Thet

    2017-06-01

    The Plasmodium falciparum Lactate Dehydrogenase enzyme (PfLDH) catalyzes inter-conversion of pyruvate to lactate during glycolysis producing the energy required for parasitic growth. The PfLDH has been studied as a potential molecular target for development of anti-malarial agents. In an attempt to find the potent inhibitor of PfLDH, we have used Discovery studio to perform molecular docking in the active binding pocket of PfLDH by CDOCKER, followed by three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of tricyclic guanidine batzelladine compounds, which were previously synthesized in our laboratory. Docking studies showed that there is a very strong correlation between in silico and in vitro results. Based on docking results, a highly predictive 3D-QSAR model was developed with q2 of 0.516. The model has predicted r2 of 0.91 showing that predicted IC50 values are in good agreement with experimental IC50 values. The results obtained from this study revealed the developed model can be used to design new anti-malarial compounds based on tricyclic guanidine derivatives and to predict activities of new inhibitors.

  16. Molecular docking, 3D QSAR and dynamics simulation studies of imidazo-pyrrolopyridines as janus kinase 1 (JAK 1) inhibitors.

    PubMed

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

    2016-10-01

    Janus kinase 1 (JAK 1) plays a critical role in initiating responses to cytokines by the JAK-signal transducer and activator of transcription (JAK-STAT). This controls survival, proliferation and differentiation of a variety of cells. Docking, 3D quantitative structure activity relationship (3D-QSAR) and molecular dynamics (MD) studies were performed on a series of Imidazo-pyrrolopyridine derivatives reported as JAK 1 inhibitors. QSAR model was generated using 30 molecules in the training set; developed model showed good statistical reliability, which is evident from r(2)ncv and r(2)loo values. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r(2)Pred) values. Finally, molecular dynamics simulation was performed to validate docking results and MM/GBSA calculations. This facilitated us to compare binding free energies of cocrystal ligand and newly designed molecule R1. The good concordance between the docking results and CoMFA/CoMSIA contour maps afforded obliging clues for the rational modification of molecules to design more potent JAK 1 inhibitors. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. 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.

  18. 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.

  19. 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.

  20. Study of the binding affinity for corticosteroid-binding globulin (CBG) using the electron topological method (ETM) as three-dimensional quantitative structure-activity relationship (3D QSAR).

    PubMed

    Guzel, Yahya; Ozturk, Emel

    2003-10-01

    The Electron Topological Method, called ETM, is a descriptor for predicting the biological activities of molecules based on three-dimensional quantitative structure-activity relations (3D QSAR). ETM uses a modified electron topological state index to substitute for electronic properties and a topological distance for the relative distance in the molecule. It is shown that the molecular fragments responsible for this activity possess fixed electronic and geometric characteristics associated with a distinct arrangement and the steric accessibility of an oxygen atom and a group of carbon atoms. After that, it is essential to employ a linear regression analysis technique to derive a 3D QSAR model relating the biological activities to the ETM. The ETM is used to study the 3D QSAR of the corticosteroid-binding globulin (CBG) binding affinity to 31 steroids, and resulting models have a comparable to current 3D methods such as CoMFA. Though the ETM is a descriptor based on 3D topological information obtained by quantum chemical derived descriptors, give the best answer for both the similarity analysis and the statistical fitting.

  1. 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.

  2. 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.

  3. 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.

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

    PubMed Central

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

    2011-01-01

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

  5. 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.

  6. 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. © 2014 John Wiley & Sons A/S.

  7. 3D-QSAR modeling and molecular docking studies on a series of 2,5 disubstituted 1,3,4-oxadiazoles

    NASA Astrophysics Data System (ADS)

    Ghaleb, Adib; Aouidate, Adnane; Ghamali, Mounir; Sbai, Abdelouahid; Bouachrine, Mohammed; Lakhlifi, Tahar

    2017-10-01

    3D-QSAR (comparative molecular field analysis (CoMFA)) and comparative molecular similarity indices analysis (CoMSIA) were performed on novel 2,5 disubstituted 1,3,4-oxadiazoles analogues as anti-fungal agents. The CoMFA and CoMSIA models using 13 compounds in the training set gives Q2 values of 0.52 and 0.51 respectively, while R2 values of 0.92. 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 determine a three-dimensional quantitative structure-activity relationship. Based on this study a set of new molecules with high predicted activities were designed. Surflex-docking confirmed the stability of predicted molecules in the receptor.

  8. 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.

  9. GRIND-based 3D-QSAR to predict inhibitory activity for similar enzymes, OSC and SHC.

    PubMed

    Ermondi, Giuseppe; Caron, Giulia

    2008-07-01

    GRIND-based 3D-QSAR methods are widely used in modern medicinal chemistry, since they are alignment-independent and almost completely automated. Nevertheless, their efficacy in predicting different biological activities for a single data set of compounds remains to be explored. In this study we explore the capabilities and limits of ALMOND procedure to predict the inhibitor potency of a series a non-terpenoid squalenehopene cyclase (SHC) inhibitors, and compare the results with recently published results concerning oxidosqualene cyclase (OSC) inhibitor potency. The findings show that the ALMOND procedure can correctly predict both activities, despite the similar architecture of the active center cavities of the two enzymes. Moreover, the graphical results suggest that a compound to act as an OSC inhibitor should satisfy more structural requirements than those necessary to be successful as an SHC inhibitor.

  10. CoMFA/CoMSIA 3D-QSAR of pyrimidine inhibitors of Pneumocystis carinii dihydrofolate reductase.

    PubMed

    Santos-Filho, Osvaldo A; Forge, Delphine; Hoelz, Lucas V B; de Freitas, Guilherme B L; Marinho, Thiago O; Araújo, Jocley Q; Albuquerque, Magaly G; de Alencastro, Ricardo B; Boechat, Nubia

    2012-09-01

    Pneumocystis carinii is typically a non-pathogenic fungus found in the respiratory tract of healthy humans. However, it may cause P. carinii pneumonia (PCP) in people with immune deficiency, affecting mainly premature babies, cancer patients and transplant recipients, and people with acquired immunodeficiency syndrome (AIDS). In the latter group, PCP occurs in approximately 80% of patients, a major cause of death. Currently, there are many available therapies to treat PCP patients, including P. carinii dihydrofolate reductase (PcDHFR) inhibitors, such as trimetrexate (TMX), piritrexim (PTX), trimethoprim (TMP), and pyrimethamine (PMT). Nevertheless, the high percentage of adverse side effects and the limited therapeutic success of the current drug therapy justify the search for new drugs rationally planned against PCP. This work focuses on the study of pyrimidine inhibitors of PcDHFR, using both CoMFA and CoMSIA 3D-QSAR methods.

  11. 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

  12. 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.

  13. 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.

  14. 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").

  15. 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.

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. Application of High Performance Computing for Development of Highly Predictive 3D-QSAR Models

    DTIC Science & Technology

    2008-12-01

    disruption of cell membranes. We have developed a series of AMPs employing unnatural amino acids by strategically controlling the 3D...1999) The AMPs are first attracted to the surface of the membrane by the electrostatic interactions between the positively charged amino acids of...conformations and identifies the bioactive conformers that most closely correlate with the observed bioactivity. 5 Table 3: Peptide amino acid sequence

  2. 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.

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

    PubMed

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

    2012-09-24

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

  4. 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.

  5. 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.

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

    PubMed

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

    2017-05-31

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

  7. 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.

  8. 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

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

    PubMed

    Bavi, Rohit; Kumar, Raj; 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.

  10. 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.

  11. Synthesis, biological evaluation, and 3D QSAR study of 2-methyl-4-oxo-3-oxetanylcarbamic acid esters as N-acylethanolamine acid amidase (NAAA) inhibitors.

    PubMed

    Ponzano, Stefano; Berteotti, Anna; Petracca, Rita; Vitale, Romina; Mengatto, Luisa; Bandiera, Tiziano; Cavalli, Andrea; Piomelli, Daniele; Bertozzi, Fabio; Bottegoni, Giovanni

    2014-12-11

    N-(2-Oxo-3-oxetanyl)carbamic acid esters have recently been reported to be noncompetitive inhibitors of the N-acylethanolamine acid amidase (NAAA) potentially useful for the treatment of pain and inflammation. In the present study, we further explored the structure-activity relationships of the carbamic acid ester side chain of 2-methyl-4-oxo-3-oxetanylcarbamic acid ester derivatives. Additional favorable features in the design of potent NAAA inhibitors have been found together with the identification of a single digit nanomolar inhibitor. In addition, we devised a 3D QSAR using the atomic property field method. The model turned out to be able to account for the structural variability and was prospectively validated by designing, synthesizing, and testing novel inhibitors. The fairly good agreement between predictions and experimental potency values points to this 3D QSAR model as the first example of quantitative structure-activity relationships in the field of NAAA inhibitors.

  12. 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.

  13. 3D-QSAR and Molecular Docking Studies on Derivatives of MK-0457, GSK1070916 and SNS-314 as Inhibitors against Aurora B Kinase

    PubMed Central

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

    2010-01-01

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

  14. Three-dimensional QSAR analysis and design of new 1,2,4-oxadiazole antibacterials.

    PubMed

    Leemans, Erika; Mahasenan, Kiran V; Kumarasiri, Malika; Spink, Edward; Ding, Derong; O'Daniel, Peter I; Boudreau, Marc A; Lastochkin, Elena; Testero, Sebastian A; Yamaguchi, Takao; Lee, Mijoon; Hesek, Dusan; Fisher, Jed F; Chang, Mayland; Mobashery, Shahriar

    2016-02-01

    The oxadiazole antibacterials, a class of newly discovered compounds that are active against Gram-positive bacteria, target bacterial cell-wall biosynthesis by inhibition of a family of essential enzymes, the penicillin-binding proteins. Ligand-based 3D-QSAR analyses by comparative molecular field analysis (CoMFA), comparative molecular shape indices analysis (CoMSIA) and Field-Based 3D-QSAR evaluated a series of 102 members of this class. This series included inactive compounds as well as compounds that were moderately to strongly antibacterial against Staphylococcus aureus. Multiple models were constructed using different types of energy minimization and charge calculations. CoMFA derived contour maps successfully defined favored and disfavored regions of the molecules in terms of steric and electrostatic properties for substitution.

  15. 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

  16. 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.

  17. 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.

  18. Molecular interaction fields and 3D-QSAR studies of p53-MDM2 inhibitors suggest additional features of ligand-target interaction.

    PubMed

    Dezi, Cristina; Carotti, Andrea; Magnani, Matteo; Baroni, Massimo; Padova, Alessandro; Cruciani, Gabriele; Macchiarulo, Antonio; Pellicciari, Roberto

    2010-08-23

    The design and optimization of small molecule inhibitors of the murine double minute clone 2-p53 (p53-MDM2) interaction has attracted a great deal of interest as a way to novel anticancer therapies. Herein we report 3D-QSAR studies of 41 small molecule inhibitors based on the use of molecular interaction fields and docking experiments as part of an approach to generating predictive models of MDM2 affinity and shedding further light on the structural elements of the ligand-target interaction. These studies have yielded predictive models explaining much of the variance of the 41 compound training set and satisfactorily predicting with 75% success an external test set of 36 compounds. Not surprisingly, and in full agreement with previous data, inspection of the 3D-QSAR coefficients reveals that the major driving force for potent inhibition is given by the hydrophobic interaction between the inhibitors and the p53 binding cleft of MDM2. More surprisingly, and challenging previous suggestions, the projection of the 3D-QSAR coefficients back onto the experimental structures of MDM2 provides an intriguing hypothesis concerning an active role played by the N-terminal region of MDM2 in ligand binding.

  19. 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.

  20. Predicting human plasma protein binding of drugs using plasma protein interaction QSAR analysis (PPI-QSAR).

    PubMed

    Li, Haiyan; Chen, Zhuxi; Xu, Xuejun; Sui, Xiaofan; Guo, Tao; Liu, Wei; Zhang, Jiwen

    2011-09-01

    A novel method, named as the plasma protein-interaction QSAR analysis (PPI-QSAR) was used to construct the QSAR models for human plasma protein binding. The intra-molecular descriptors of drugs and inter-molecular interaction descriptors resulted from the docking simulation between drug molecules and human serum albumin were included as independent variables in this method. A structure-based in silico model for a data set of 65 antibiotic drugs was constructed by the multiple linear regression method and validated by the residual analysis, the normal Probability-Probability plot and Williams plot. The R(2) and Q(2) values of the entire data set were 0.87 and 0.77, respectively, for the training set were 0.86 and 0.72, respectively. The results indicated that the fitted model is robust, stable and satisfies all the prerequisites of the regression models. Combining intra-molecular descriptors with inter-molecular interaction descriptors between drug molecules and human serum albumin, the drug plasma protein binding could be modeled and predicted by the PPI-QSAR method successfully.

  1. Megavariate analysis of hierarchical QSAR data

    NASA Astrophysics Data System (ADS)

    Eriksson, Lennart; Johansson, Erik; Lindgren, Fredrik; Sjöström, Michael; Wold, Svante

    2002-10-01

    Multivariate PCA- and PLS-models involving many variables are often difficult to interpret, because plots and lists of loadings, coefficients, VIPs, etc, rapidly become messy and hard to overview. There may then be a strong temptation to eliminate variables to obtain a smaller data set. Such a reduction of variables, however, often removes information and makes the modelling efforts less reliable. Model interpretation may be misleading and predictive power may deteriorate. A better alternative is usually to partition the variables into blocks of logically related variables and apply hierarchical data analysis. Such blocked data may be analyzed by PCA and PLS. This modelling forms the base-level of the hierarchical modelling set-up. On the base-level in-depth information is extracted for the different blocks. The score vectors formed on the base-level, here called `super variables', may be linked together in new matrices on the top-level. On the top-level superficial relationships between the X- and the Y-data are investigated. In this paper the basic principles of hierarchical modelling by means of PCA and PLS are reviewed. One objective of the paper is to disseminate this concept to a broader QSAR audience. The hierarchical methods are used to analyze a set of 10 haloalkanes for which K = 30 chemical descriptors and M = 255 biological responses have been gathered. Due to the complexity of the biological data, they are sub-divided in four blocks. All the modelling steps on the base-level and the top-level are reported and the final QSAR model is interpreted thoroughly.

  2. 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.

  3. 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

  4. 3D QSAR based design of novel oxindole derivative as 5HT7 inhibitors.

    PubMed

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

    2014-06-01

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

  5. A Mechanism-based 3D-QSAR Approach for Classification ...

    EPA Pesticide Factsheets

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π–π interaction with Trp86

  6. A Mechanism-based 3D-QSAR Approach for Classification ...

    EPA Pesticide Factsheets

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π–π interaction with Trp86

  7. 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.

  8. 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.

  9. 3D space analysis of dental models

    NASA Astrophysics Data System (ADS)

    Chuah, Joon H.; Ong, Sim Heng; Kondo, Toshiaki; Foong, Kelvin W. C.; Yong, Than F.

    2001-05-01

    Space analysis is an important procedure by orthodontists to determine the amount of space available and required for teeth alignment during treatment planning. Traditional manual methods of space analysis are tedious and often inaccurate. Computer-based space analysis methods that work on 2D images have been reported. However, as the space problems in the dental arch exist in all three planes of space, a full 3D analysis of the problems is necessary. This paper describes a visualization and measurement system that analyses 3D images of dental plaster models. Algorithms were developed to determine dental arches. The system is able to record the depths of the Curve of Spee, and quantify space liabilities arising from a non-planar Curve of Spee, malalignment and overjet. Furthermore, the difference between total arch space available and the space required to arrange the teeth in ideal occlusion can be accurately computed. The system for 3D space analysis of the dental arch is an accurate, comprehensive, rapid and repeatable method of space analysis to facilitate proper orthodontic diagnosis and treatment planning.

  10. From Molecular Docking to 3D-Quantitative Structure-Activity Relationships (3D-QSAR): Insights into the Binding Mode of 5-Lipoxygenase Inhibitors.

    PubMed

    Eren, Gokcen; Macchiarulo, Antonio; Banoglu, Erden

    2012-02-01

    Pharmacological intervention with 5-Lipoxygenase (5-LO) is a promising strategy for treatment of inflammatory and allergic ailments, including asthma. With the aim of developing predictive models of 5-LO affinity and gaining insights into the molecular basis of ligand-target interaction, we herein describe QSAR studies of 59 diverse nonredox-competitive 5-LO inhibitors based on the use of molecular shape descriptors and docking experiments. These studies have successfully yielded a predictive model able to explain much of the variance in the activity of the training set compounds while predicting satisfactorily the 5-LO inhibitory activity of an external test set of compounds. The inspection of the selected variables in the QSAR equation unveils the importance of specific interactions which are observed from docking experiments. Collectively, these results may be used to design novel potent and selective nonredox 5-LO inhibitors. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. 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

    2017-06-01

    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.

  12. 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.

  13. Combined 3D-QSAR, molecular docking, and molecular dynamics study of tacrine derivatives as potential acetylcholinesterase (AChE) inhibitors of Alzheimer's disease.

    PubMed

    Zhou, An; Hu, Jianping; Wang, Lirong; Zhong, Guochen; Pan, Jian; Wu, Zeyu; Hui, Ailing

    2015-10-01

    Acetylcholinesterase (AChE) is one of the key targets of drugs for treating Alzheimer's disease (AD). Tacrine is an approved drug with AChE-inhibitory activity. In this paper, 3D-QSAR, molecular docking, and molecular dynamics were carried out in order to study 60 tacrine derivatives and their AChE-inhibitory activities. 3D-QSAR modeling resulted in an optimal CoMFA model with q(2) = 0.552 and r(2) = 0.983 and an optimal CoMSIA model with q(2) = 0.581 and r(2) = 0.989. These QSAR models also showed that the steric and H-bond fields of these compounds are important influences on their activities. The interactions between these inhibitors and AChE were further explored through molecular docking and molecular dynamics simulation. A few key residues (Tyr70, Trp84, Tyr121, Trp279, and Phe330) at the binding site of AChE were identified. The results of this study improve our understanding of the mechanisms of AChE inhibitors and afford valuable information that should aid the design of novel potential AChE inhibitors. Graphical Abstract Superposition of backbone atoms of the lowest-energy structure obtained from MD simulation (magenta) onto those of the structure of the initial molecular docking model (green).

  14. 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.

  15. 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.

  16. 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.

  17. Molecular modeling studies to characterize N-phenylpyrimidin-2-amine selectivity for CDK2 and CDK4 through 3D-QSAR and molecular dynamics simulations.

    PubMed

    Chohan, Tahir Ali; Chen, Jiong-Jiong; Qian, Hai-Yan; Pan, You-Lu; Chen, Jian-Zhong

    2016-04-01

    CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the selectivity mechanism against CDK4 using a combined approach of 3D-QSAR, molecular docking, MESP, MD simulations, and binding free energy calculations. 3D-QSAR models were developed to propose structural determinants for CDK2 and CDK4 inhibition. High q(2) and r(2) values for CoMFA and CoMSIA models based on both internal and external validations suggested that the generated 3D-QSAR models may exhibit good capability to predict bioactivities of inhibitors against CDK2 or CDK4. Electrostatic potentials on the molecular surface have been discussed in detail for determining the binding affinity of studied inhibitors by combining molecular docking with MESP and Mulliken charge analyses. Binding free energy calculations suggested that the residues Gln85, Asp86, and Lys89 of CDK2 would play a critical role in selective CDK2 inhibition. The electrostatic interactions of an inhibitor with Glu144 and Asn145 of CDK4 may predominately drive CDK4 inhibition. These findings may provide a better structural understanding of the mechanism of CDK2 selective inhibition. The results obtained in the current study may provide valuable guidelines for developing novel potent and selective CDK2 inhibitors.

  18. 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. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. 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.

  20. 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.

  1. 3D-QSAR (CoMFA, CoMSIA), molecular docking and molecular dynamics simulations study of 6-aryl-5-cyano-pyrimidine derivatives to explore the structure requirements of LSD1 inhibitors.

    PubMed

    Ding, Lina; Wang, Zhi-Zheng; Sun, Xu-Dong; Yang, Jing; Ma, Chao-Ya; Li, Wen; Liu, Hong-Min

    2017-08-01

    Recently, Histone Lysine Specific Demethylase 1 (LSD1) was regarded as a promising anticancer target for the novel drug discovery. And several small molecules as LSD1 inhibitors in different structures have been reported. In this work, we carried out a molecular modeling study on the 6-aryl-5-cyano-pyrimidine fragment LSD1 inhibitors using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulations. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. The results show that the best CoMFA model has q(2)=0.802, r(2)ncv=0.979, and the best CoMSIA model has q(2)=0.799, r(2)ncv=0.982. The electrostatic, hydrophobic and H-bond donor fields play important roles in the models. Molecular docking studies predict the binding mode and the interactions between the ligand and the receptor protein. Molecular dynamics simulations results reveal that the complex of the ligand and the receptor protein are stable at 300K. All the results can provide us more useful information for our further drug design. Copyright © 2017. Published by Elsevier Ltd.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 3-D analysis of grain selection process

    NASA Astrophysics Data System (ADS)

    Arao, Tomoka; Esaka, Hisao; Shinozuka, Kei

    2012-07-01

    It is known that the grain selection plays an important role in the manufacturing process for turbine blades. There are some analytical or numerical models to treat the grain selection. However, the detailed mechanism of grain selection in 3-D is still uncertain. Therefore, an experimental research work using Al-Cu alloy has been carried out in order to understand the grain selection in 3-D.A mold made by Al2O3 was heated to 600 °C ( = liquids temperature of the alloy) and was set on a water-colded copper chill plate. Molten Al-20 wt%Cu alloy was cast into the mold and unidirectional solidified ingot was prepared. The size of ingot was approximately phi25×65H mm. To obtain the thermal history, 4 thermocouples were placed in the mold. It is confirmed that the alloy solidified unidirectionally from bottom to top. Solidified structure on a longitudinal cross section was observed and unidirectional solidification up to 40 mm was ensured. EBSD analysis has been performed on horizontal cross section at an interval of ca.200 μm. These observations were carried out 7-5 mm from the bottom surface. Crystallographic orientation of primary Al phase and size of solidified grains were characterized. A large solidified grain, the crystallographic orientation of which is approximately <101> along heat flow direction, is observed near the lowest cross section. The area of <101> grain decreased as solidification proceeded. On the other hand, it is found that the area of <001> grain increased.

  7. Evaluation of reproducibility and reliability of 3D soft tissue analysis using 3D stereophotogrammetry.

    PubMed

    Plooij, J M; Swennen, G R J; Rangel, F A; Maal, T J J; Schutyser, F A C; Bronkhorst, E M; Kuijpers-Jagtman, A M; Bergé, S J

    2009-03-01

    In 3D photographs the bony structures are neither available nor palpable, therefore, the bone-related landmarks, such as the soft tissue gonion, need to be redefined. The purpose of this study was to determine the reproducibility and reliability of 49 soft tissue landmarks, including newly defined 3D bone-related soft tissue landmarks with the use of 3D stereophotogrammetric images. Two observers carried out soft-tissue analysis on 3D photographs twice for 20 patients. A reference frame and 49 landmarks were identified on each 3D photograph. Paired Student's t-test was used to test the reproducibility and Pearson's correlation coefficient to determine the reliability of the landmark identification. Intra- and interobserver reproducibility of the landmarks were high. The study showed a high reliability coefficient for intraobserver (0.97 (0.90 - 0.99)) and interobserver reliability (0.94 (0.69 - 0.99)). Identification of the landmarks in the midline was more precise than identification of the paired landmarks. In conclusion, the redefinition of bone-related soft tissue 3D landmarks in combination with the 3D photograph reference system resulted in an accurate and reliable 3D photograph based soft tissue analysis. This shows that hard tissue data are not needed to perform accurate soft tissue analysis.

  8. 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.

  9. 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.

  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. 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.

  12. 3D face analysis for demographic biometrics

    SciTech Connect

    Tokola, Ryan A; Mikkilineni, Aravind K; Boehnen, Chris Bensing

    2015-01-01

    Despite being increasingly easy to acquire, 3D data is rarely used for face-based biometrics applications beyond identification. Recent work in image-based demographic biometrics has enjoyed much success, but these approaches suffer from the well-known limitations of 2D representations, particularly variations in illumination, texture, and pose, as well as a fundamental inability to describe 3D shape. This paper shows that simple 3D shape features in a face-based coordinate system are capable of representing many biometric attributes without problem-specific models or specialized domain knowledge. The same feature vector achieves impressive results for problems as diverse as age estimation, gender classification, and race classification.

  13. Multifractal modelling and 3D lacunarity analysis

    NASA Astrophysics Data System (ADS)

    Hanen, Akkari; Imen, Bhouri; Asma, Ben Abdallah; Patrick, Dubois; Hédi, Bedoui Mohamed

    2009-09-01

    This study presents a comparative evaluation of lacunarity of 3D grey level models with different types of inhomogeneity. A new method based on the “Relative Differential Box Counting” was developed to estimate the lacunarity features of grey level volumes. To validate our method, we generated a set of 3D grey level multifractal models with random, anisotropic and hierarchical properties. Our method gives a lacunarity measurement correlated with the theoretical one and allows a better model classification compared with a classical approach.

  14. 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.

  15. 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.

  16. 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.

  17. GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers.

    PubMed

    Ermondi, Giuseppe; Visentin, Sonja; Caron, Giulia

    2009-05-01

    The study compares GRIND-based 3D-QSAR and CoMFA [A. Cavalli, E. Poluzzi, F. De Ponti, M. Recanatini, J. Med. Chem, 45(2002), 3844-53] to investigate a biological topic dominated by hydrophobic interactions, e.g. hERG K(+) channel blocking activity. As expected, models are found by both methods and there is a fine agreement between statistical and graphical results as well. However, a closer inspection revealed that failures in the prediction of hERG blocking activity for lipophilic compounds were registered for both methods. The study explores the reasons for these failures which are strongly dependent on the chosen method, and gives some suggestions to handle with these topics.

  18. 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.

  19. The development of 3D-QSAR study and recursive partitioning of heterocyclic quinone derivatives with antifungal activity.

    PubMed

    Choi, Su-Young; Shin, Jae Hong; Ryu, Chung Kyu; Nam, Ky-Youb; No, Kyoung Tai; Park Choo, Hea-Young

    2006-03-01

    It was reported that some 1,4-quinone derivatives such as 6-(N-arylamino)-7-chloro/6,7-bis[S-(aryl)thio]-5,8-quinolinedione and 6-arylthio-/5,6-arylamino-4,7-dioxobenzothiazoles have antifungal effects. To understand the structural basis for antifungal activity and guide in the design of more potent agents, we performed three-dimensional quantitative structure-activity relationship studies for a series of compounds using comparative molecular field analysis (CoMFA). The MIC values of 1,4-quinone derivatives on Aspergillus niger exhibited a strong correlation with steric and electrostatic factors of the 3D structure of molecules. The statistical results of the training set, cross-validated q(2) (0.683) and conventional r(2) (0.877) values, gave reliability to the prediction of inhibitory activity of a series of compounds. We also performed recursive partitioning (RP) analysis, used for the classification of molecules with activity using CART methods. Physicochemical, structural, and topological connectivity indices and E-state key descriptors were used for obtaining the decision tree models. The decision tree could classify the inhibitory activity of 1,4-quinone derivatives and its essential descriptors were S_aaN, Hbond donor, and Kappa-3.

  20. Comparative QSAR analysis of cyclo-oxygenase2 inhibiting drugs.

    PubMed

    Mohanapriya, Arumugam; Achuthan, Dayalan

    2012-01-01

    Cyclo-oxygenase 2 (COX2) inhibiting drugs were subjected to comparative quantitative structure activity relationship (QSAR) analysis with an attempt to derive and to understand the relationship between the biological activity and molecular descriptors by multiple regression analysis. The different drugs that inhibit cyclo-oxygenase 2 enzyme were compared instead of subjecting one drug and its derivatives to QSAR analysis. The study was conducted to look for the common structural features between the drugs which confer to a good biological activity. Based on the regression analysis the following descriptors were finalized as the components fitting best in the regression equations: Ss, SCBO, RBN, nN, SIC0, IC1, and H-055. These descriptors belong to constitution (Ss, SCBO, RBN, nN), information indices (SIC0, IC1) and atom centered fragments (H-055) category. Based on these descriptors QSAR models were generated and evaluated for best structure-activity correlation. The model generated from constitution and information indices descriptors corresponds to the essential structural features of the drugs and are found to have significant correlation with COX2 inhibiting activity. This study shall help in rational drug design and synthesis of new selective cyclo-oxygenase 2 inhibitors with predetermined affinity and activity.

  1. Tilted planes in 3D image analysis

    NASA Astrophysics Data System (ADS)

    Pargas, Roy P.; Staples, Nancy J.; Malloy, Brian F.; Cantrell, Ken; Chhatriwala, Murtuza

    1998-03-01

    Reliable 3D wholebody scanners which output digitized 3D images of a complete human body are now commercially available. This paper describes a software package, called 3DM, being developed by researchers at Clemson University and which manipulates and extracts measurements from such images. The focus of this paper is on tilted planes, a 3DM tool which allows a user to define a plane through a scanned image, tilt it in any direction, and effectively define three disjoint regions on the image: the points on the plane and the points on either side of the plane. With tilted planes, the user can accurately take measurements required in applications such as apparel manufacturing. The user can manually segment the body rather precisely. Tilted planes assist the user in analyzing the form of the body and classifying the body in terms of body shape. Finally, titled planes allow the user to eliminate extraneous and unwanted points often generated by a 3D scanner. This paper describes the user interface for tilted planes, the equations defining the plane as the user moves it through the scanned image, an overview of the algorithms, and the interaction of the tilted plane feature with other tools in 3DM.

  2. 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

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

    PubMed

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

    2017-10-01

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

  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. Elastoplastic shell analysis in DYNA3D

    SciTech Connect

    Whirley, R.G. )

    1991-01-01

    Computer simulation of the elastoplastic behavior of thin shell structures under transient dynamic loads play an important role in many programs at Lawrence Livermore National Laboratory (LLNL) in Livermore, Calif. Often the loads are severe and the structure undergoes plastic (or permanent) deformation. These simulations are effectively performed using DYNA3D, an explicit nonlinear finite element code developed at LLNL for simulating and analyzing the large-deformation dynamic response of solids and structures. It is generally applicable to problems where the loading and response are of short duration and contain significant high-frequency components. Typical problems of this type include the contact of two impacting bodies and the resulting elastoplastic structural behavior. The objective of this investigation was to examine and improve upon the elastoplastic shell modeling capability in DYNA3D. This article summarizes the development of a new four-node quadrilateral finite element shell formulation, the YASE shell, and compares two basic methods (the stress-resultant and the thickness-resultant methods) employed in elastoplastic constitutive algorithms for shell structure modeling.

  6. 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.

  7. Motion analysis using 3D high-resolution frequency analysis.

    PubMed

    Ueda, Takaaki; Fujii, Kenta; Hirobayashi, Shigeki; Yoshizawa, Toshio; Misawa, Tadanobu

    2013-08-01

    The spatiotemporal spectra of a video that contains a moving object form a plane in the 3D frequency domain. This plane, which is described as the theoretical motion plane, reflects the velocity of the moving objects, which is calculated from the slope. However, if the resolution of the frequency analysis method is not high enough to obtain actual spectra from the object signal, the spatiotemporal spectra disperse away from the theoretical motion plane. In this paper, we propose a high-resolution frequency analysis method, described as 3D nonharmonic analysis (NHA), which is only weakly influenced by the analysis window. In addition, we estimate the motion vectors of objects in a video using the plane-clustering method, in conjunction with the least-squares method, for 3D NHA spatiotemporal spectra. We experimentally verify the accuracy of the 3D NHA and its usefulness for a sequence containing complex motions, such as cross-over motion, through comparison with 3D fast Fourier transform. The experimental results show that increasing the frequency resolution contributes to high-accuracy estimation of a motion plane.

  8. 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

  9. 3D joint dynamics analysis of healthy children's gait.

    PubMed

    Samson, William; Desroches, Guillaume; Cheze, Laurence; Dumas, Raphaël

    2009-11-13

    The 3D joint moments and 2D joint powers have been largely explored in the literature of healthy children's gait, in particular to compare them with pathologic subjects' gait. However, no study reported on 3D joint power in children which could be due to the difficulties in interpreting the results. Recently, the analysis of the 3D angle between the joint moment and the joint angular velocity vectors has been proposed in order to help 3D joint power interpretation. Our hypothesis is that this 3D angle may help in characterizing the level of gait maturation. The present study explores 3D joint moments, 3D joint power and the proposed 3D angle for both children's and adults' gaits to highlight differences in the strategies used. The results seem to confirm that children have an alternative strategy of mainly ankle stabilization and hip propulsion compared to the adults' strategy of mainly ankle resistance and propulsion and hip stabilization. In the future, the same 3D angle analysis should be applied to different age groups for better describing the evolution of the 3D joint dynamic strategies during the growth.

  10. 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

  11. New software for 3D fracture network analysis and visualization

    NASA Astrophysics Data System (ADS)

    Song, J.; Noh, Y.; Choi, Y.; Um, J.; Hwang, S.

    2013-12-01

    This study presents new software to perform analysis and visualization of the fracture network system in 3D. The developed software modules for the analysis and visualization, such as BOUNDARY, DISK3D, FNTWK3D, CSECT and BDM, have been developed using Microsoft Visual Basic.NET and Visualization TookKit (VTK) open-source library. Two case studies revealed that each module plays a role in construction of analysis domain, visualization of fracture geometry in 3D, calculation of equivalent pipes, production of cross-section map and management of borehole data, respectively. The developed software for analysis and visualization of the 3D fractured rock mass can be used to tackle the geomechanical problems related to strength, deformability and hydraulic behaviors of the fractured rock masses.

  12. A 3D-QSAR Study on Betulinic Acid Derivatives as Anti-Tumor Agents and the Synthesis of Novel Derivatives for Modeling Validation.

    PubMed

    Ding, Weimin; Zhang, Sheng; Zhu, Meixuan; Wang, Shaoming; Xu, Tao; Qu, Haijing; Yu, Tao; Yan, Xiufeng; Wang, Yang

    2017-01-01

    Betulinic acid is a lupane-type triterpene firstly extracted from the bark of white birch. It has displayed anti-inflammatory, antioxidant, anti-HIV and selective cytotoxicity. To understand the structure- anti-tumor activity relationship of betulinic acid and betulin derivatives and to synthesize novel anti-tumor derivatives of betulinic acid and betulin. The 3D-QSAR methods including CoMFA and CoMSIA methods were performed to study the structureanti- tumor activity relationship of betulinic acid (BA) and betulin (BE) derivatives. According to the models, near the C-3 site, non-bulky, negatively charged electron-donating, hydrophobic, non-hydrogen-bond-donating and hydrogen-bond-accepting groups are favored to the activity. Around the C-28 site, the bulky, positively charged electron-withdrawing and hydrophobic groups are favored, whereas hydrophilic groups may be introduced at the terminal of the side chain. Based on the models, BA and BE were esterified with substituted amino acid derivatives achieving novel derivatives for the modeling validation. The experimental results verified the modeling rules, and showed when different rules may apply to the new structures, the steric effects might be more important. The synthesized derivatives were showed promising cytotoxicity against tested cancer cell lines. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 3D Frame Buffers For Interactive Analysis Of 3D Data

    NASA Astrophysics Data System (ADS)

    Hunter, Gregory M.

    1984-10-01

    Two-dimensional data such as photos, X rays, various types of satellite images, sonar, radar, seismic plots, etc., in many cases must be analyzed using frame buffers for purposes of medical diagnoses, crop estimates, mineral exploration, and so forth. In many cases the same types of sensors used to gather such samples in two dimensions can gather 3D data for even more effective analysis. Just as 2D arrays of data can be analyzed using frame buffers, three-dimensional data can be analyzed using SOLIDS-BUFFEPmemories. Image processors deal with samples from two-dimensional arrays, and are based on frame buffers. The SOLIDS PROCESSOR system, deals with samples from a three-dimensional volume, or solid, and is based on a 3D frame buffer. This paper focuses upon the SOLIDS-BUFFER system, as used in the INSIGHT SOLIDS-PROCESSOR system from Phoenix Data Systems.

  18. Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors

    PubMed Central

    2011-01-01

    Background Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study. Methods Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features. Results The best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors. Conclusion A quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were

  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. a Novel Approach for 3d Neighbourhood Analysis

    NASA Astrophysics Data System (ADS)

    Emamgholian, S.; Taleai, M.; Shojaei, D.

    2017-09-01

    Population growth and lack of land in urban areas have caused massive developments such as high rises and underground infrastructures. Land authorities in the international context recognizes 3D cadastres as a solution to efficiently manage these developments in complex cities. Although a 2D cadastre does not efficiently register these developments, it is currently being used in many jurisdictions for registering land and property information. Limitations in analysis and presentation are considered as examples of such limitations. 3D neighbourhood analysis by automatically finding 3D spaces has become an issue of major interest in recent years. Whereas the neighbourhood analysis has been in the focus of research, the idea of 3D neighbourhood analysis has rarely been addressed in 3 dimensional information systems (3D GIS) analysis. In this paper, a novel approach for 3D neighbourhood analysis has been proposed by recording spatial and descriptive information of the apartment units and easements. This approach uses the coordinates of the subject apartment unit to find the neighbour spaces. By considering a buffer around the edges of the unit, neighbour spaces are accurately detected. This method was implemented in ESRI ArcScene and three case studies were defined to test the efficiency of this approach. The results show that spaces are accurately detected in various complex scenarios. This approach can also be applied for other applications such as property management and disaster management in order to find the affected apartments around a defined space.

  1. Structural insights of SmKDAC8 inhibitors: Targeting Schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy.

    PubMed

    Ballante, Flavio; Reddy, D Rajasekhar; Zhou, Nancy J; Marshall, Garland R

    2017-04-01

    A predictive structure-based 3D QSAR (COMBINEr 2.0) model of the Schistosoma mansoni lysine deacetylase 8 enzyme (SmKDAC8) was developed, validated and used to perform virtual screening (VS) of the NCI Diversity Set V database (1593 compounds). Three external datasets (with congeneric structures to those experimentally resolved in complexes by X-ray and previously reported as SmKDAC8 inhibitors) were employed to compose and validate the most predictive model. Two series characterized by 104 benzodiazepine derivatives (BZDs) and 60 simplified largazole analogs (SLAs), recently reported by our group as human KDAC inhibitors, were tested for their inhibition potency against SmKDAC8 to probe the predictive capability of the quantitative models against compounds with diverse structures. The SmKDAC8 biochemical results confirmed: (1) the benzodiazepine moiety as a valuable scaffold to further investigate when pursuing SmKDAC8 inhibition; (2) the predictive capability of the COMBINEr 2.0 model towards non-congeneric series of compounds, highlighting the most influencing ligand-protein interactions and refining the structure-activity relationships. From the VS investigations, the first 40 top-ranked compounds were obtained and biologically tested for their inhibition potency against SmKDAC8 and hKDACs 1, 3, 6 and 8. Among them, a non-hydroxamic acid benzothiadiazine dioxide derivative (code NSC163639), showed interesting activity and selectivity against SmKDAC8. To further elucidate the structure-activity relationships of NSC163639, two analogs (herein reported as compounds 3 and 4) were synthesized and biologically evaluated. Results suggest the benzothiadiazine dioxide moiety as a promising scaffold to be used in a next step to derive selective SmKDAC8 inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.

    PubMed

    Diniz, Evelyn Mirella Lopes Pina; Tomich de Paula da Silva, Carlos Henrique; Gómez-Perez, Verónica; Federico, Leonardo Bruno; Campos Rosa, Joaquín María

    2017-08-01

    Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6β3β4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.

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

    PubMed Central

    Cramer, Richard D.

    2015-01-01

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

  4. Modifying tetramethyl–nitrophenyl–imidazoline with amino acids: design, synthesis, and 3D-QSAR for improving inflammatory pain therapy

    PubMed Central

    Jiang, Xueyun; Wang, Yuji; Zhu, Haimei; Wang, Yaonan; Zhao, Ming; Zhao, Shurui; Wu, Jianhui; Li, Shan; Peng, Shiqi

    2015-01-01

    With the help of pharmacophore analysis and docking investigation, 15 novel 1-(4,4,5,5-tetramethyl-2-(3-nitrophenyl)-4,5-dihydroimidazol-1-yl)-oxyacetyl-L-amino acids (6a–o) were designed, synthesized, and assayed. On tail-flick and xylene-induced ear edema models, 10 μmol/kg 6a–o exhibited excellent oral anti-inflammation and analgesic activity. The dose-dependent assay of their representative 6f indicates that the effective dose should be 3.3 μmol/kg. The correlation of the three-dimensional quantitative structure–activity relationship with the docking analysis provides a basis for the rational design of drugs to treat inflammatory pain. PMID:25960636

  5. 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.

  6. 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

  7. 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation of Pseudomonas aeruginosa LpxC Inhibitors.

    PubMed

    Zuo, Ke; Liang, Li; Du, Wenyi; Sun, Xin; Liu, Wei; Gou, Xiaojun; Wan, Hua; Hu, Jianping

    2017-05-06

    As an important target for the development of novel antibiotics, UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) has been widely studied. Pyridone methylsulfone hydroxamate (PMH) compounds can effectively inhibit the catalytic activity of LpxC. In this work, the three-dimensional quantitative structure-activity relationships of PMH inhibitors were explored and models with good predictive ability were established using comparative molecular field analysis and comparative molecular similarity index analysis methods. The effect of PMH inhibitors' electrostatic potential on the inhibitory ability of Pseudomonas aeruginosa LpxC (PaLpxC) is revealed at the molecular level via molecular electrostatic potential analyses. Then, two molecular dynamics simulations for the PaLpxC and PaLpxC-inhibitor systems were also performed respectively to investigate the key residues of PaLpxC hydrolase binding to water molecules. The results indicate that orderly alternative water molecules can form stable hydrogen bonds with M62, E77, T190, and H264 in the catalytic center, and tetracoordinate to zinc ion along with H78, H237, and D241. It was found that the conformational transition space of PaLpxC changes after association with PMH inhibitors through free energy landscape and cluster analyses. Finally, a possible inhibitory mechanism of PMH inhibitors was proposed, based on our molecular simulation. This paper will provide a theoretical basis for the molecular design of LpxC-targeting antibiotics.

  8. Analysis of 3D branching pattern: hematoxylin and eosin method.

    PubMed

    Sims-Lucas, Sunder

    2012-01-01

    Accurate analysis of the three-dimensional (3D) architecture of developing organs is critical to understanding how developmental defects can be linked with structural abnormalities. Here, we describe a 3D reconstruction technique of the developing kidney including the outer kidney capsule, ureteric epithelium, and developing nephrons. This 3D reconstructive process involves generating serial sections of the developing kidney, followed by histological staining. Each serial image is projected on the monitor and each tissue lineage or structure is traced. The kidney tracings are aligned and a 3D image is rendered. Each reconstructed tissue/lineage can then be subjected to quantitative analysis (e.g., surface area or volume). The reconstructed ureteric epithelium can be skeletonized to determine the branching architecture.

  9. 3D-QSAR, molecular dynamics simulations, and molecular docking studies on pyridoaminotropanes and tetrahydroquinazoline as mTOR inhibitors.

    PubMed

    Chaube, Udit; Bhatt, Hardik

    2017-06-02

    Cancer is a second major disease after metabolic disorders where the number of cases of death is increasing gradually. Mammalian target of rapamycin (mTOR) is one of the most important targets for treatment of cancer, specifically for breast and lung cancer. In the present research work, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) studies were performed on 50 compounds reported as mTOR inhibitors. Three different alignment methods were used, and among them, distill method was found to be the best method. In CoMFA, leave-one-out cross-validated coefficients [Formula: see text], conventional coefficient [Formula: see text], and predicted correlation coefficient [Formula: see text] values were found to be 0.664, 0.992, and 0.652, respectively. CoMSIA study was performed in 25 different combinations of features, such as steric, electrostatic, hydrogen bond donor, hydrogen bond acceptor, and hydrophobic. From this, a combination of steric, electrostatic, hydrophobic (SEH), and a combination of steric, electrostatic, hydrophobic, donor, and acceptor (SEHDA) were found as best combinations. In CoMSIA (SEHDA), [Formula: see text], [Formula: see text] and [Formula: see text] were found to be 0.646, 0.977, and 0.682, respectively, while in the case of CoMSIA (SEH), the values were 0.739, 0.976, and 0.779, respectively. Contour maps were generated and validated by molecular dynamics simulation-assisted molecular docking study. Highest active compound 19, moderate active compound 15, and lowest active compound 42 were docked on mTOR protein to validate the results of our molecular docking study. The result of the molecular docking study of highest active compound 19 is in line with the outcomes generated by contour maps. Based on the features obtained through this study, six novel mTOR inhibitors were designed and docked. This study could be useful for designing novel molecules with increased anticancer activity.

  10. 3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines.

    PubMed

    Yu, Zhuang; Li, Xianchao; Ge, Cuizhu; Si, Hongzong; Cui, Lianhua; Gao, Hua; Duan, Yunbo; Zhai, Honglin

    2015-02-01

    Mer kinase is a novel therapeutic target for many cancers, and overexpression of Mer receptor tyrosine kinase has been observed in several kinds of tumors. To deeply understand the structure-activity correlation of a series of pyridine/pyrimidine analogs as potent Mer inhibitors, a combined molecular docking and three-dimensional quantitative structure-activity relationship modeling was carried out. A comparative molecular similarity indices analysis model was developed based on the maximum common substructure alignment. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.599, and non-cross-validated r2 value was 0.984. Furthermore, the results of internal validation such as bootstrapping, Y-randomization as well as external validation (the external predictive correlation coefficient r2 ext = 0.728) confirmed the rationality and good predictive ability of the model. Using the crystal structure of Mer kinase, the selected pyridine/pyrimidine compounds were docked into the enzyme active site. Some key amino acid residues were determined, and hydrogen bonding and hydrophobic interactions between Mer kinase and inhibitors were identified. The satisfactory results from this study may aid in the research and development of novel potent Mer kinase inhibitors.

  11. 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.

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

    NASA Astrophysics Data System (ADS)

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

    2017-07-01

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

  13. Some remarks on shell element analysis with DYNA3D and NIKE3D

    NASA Astrophysics Data System (ADS)

    Whirley, R. G.; Engelmann, B. E.; Maker, B. N.; Spelce, T. E.

    1992-03-01

    There has been some confusion in the user community recently regarding the various shell element formulations now available in DYNA3D (Whirley and Hadlquist, 1991) and NIKE3D (Maker, Ferencz, and Hallquist, 1991). In particular, questions have been raised about the behavior of these elements under large strain, and the display of meaningful results from such problems using TAURUS (Spelce and Hallquist, 1991). This brief report is intended to aid the DYNA/NIKE user community by elaborating on the formulation of the DYNA3D/NIKE3D shell elements and on the display of shell data using TAURUS. In the following discussion no attempt is made to give a complete description of the theoretical development or implementation of any of the elements. Readers interested in a more complete discussion of the shell elements in DYNA3D and NIKE3D are directed to the published papers cited in the code User Manuals.

  14. 3-D object-oriented image analysis of geophysical data

    NASA Astrophysics Data System (ADS)

    Fadel, I.; Kerle, N.; van der Meijde, M.

    2014-07-01

    Geophysical data are the main source of information about the subsurface. Geophysical techniques are, however, highly non-unique in determining specific physical parameters and boundaries of subsurface objects. To obtain actual physical information, an inversion process is often applied, in which measurements at or above the Earth surface are inverted into a 2- or 3-D subsurface spatial distribution of the physical property. Interpreting these models into structural objects, related to physical processes, requires a priori knowledge and expert analysis which is susceptible to subjective choices and is therefore often non-repeatable. In this research, we implemented a recently introduced object-based approach to interpret the 3-D inversion results of a single geophysical technique using the available a priori information and the physical and geometrical characteristics of the interpreted objects. The introduced methodology is semi-automatic and repeatable, and allows the extraction of subsurface structures using 3-D object-oriented image analysis (3-D OOA) in an objective knowledge-based classification scheme. The approach allows for a semi-objective setting of thresholds that can be tested and, if necessary, changed in a very fast and efficient way. These changes require only changing the thresholds used in a so-called ruleset, which is composed of algorithms that extract objects from a 3-D data cube. The approach is tested on a synthetic model, which is based on a priori knowledge on objects present in the study area (Tanzania). Object characteristics and thresholds were well defined in a 3-D histogram of velocity versus depth, and objects were fully retrieved. The real model results showed how 3-D OOA can deal with realistic 3-D subsurface conditions in which the boundaries become fuzzy, the object extensions become unclear and the model characteristics vary with depth due to the different physical conditions. As expected, the 3-D histogram of the real data was

  15. USJ metrology: from 0D to 3D analysis

    SciTech Connect

    Vandervorst, Wilfried

    2007-09-26

    The analysis of ultra shallow junctions is becoming a challenging task for which numerous tools and concepts are available. The requirements range from a simple 0D-analysis such as the integral dose or the sheet resistance over a simple 1D-profile (as obtained on blanket films) towards the 2D-dopant profile within a transistor. The ultimate complexity will be the analysis of a complete 3D-structure such as a FINFET, requiring a metrology tool with 3D-resolution. In each of these areas significant progress has been made in recent years and new concepts are emerging which will be discussed in this review.

  16. 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.

  17. 3-D transient analysis of pebble-bed HTGR by TORT-TD/ATTICA3D

    SciTech Connect

    Seubert, A.; Sureda, A.; Lapins, J.; Buck, M.; Bader, J.; Laurien, E.

    2012-07-01

    As most of the acceptance criteria are local core parameters, application of transient 3-D fine mesh neutron transport and thermal hydraulics coupled codes is mandatory for best estimate evaluations of safety margins. This also applies to high-temperature gas cooled reactors (HTGR). Application of 3-D fine-mesh transient transport codes using few energy groups coupled with 3-D thermal hydraulics codes becomes feasible in view of increasing computing power. This paper describes the discrete ordinates based coupled code system TORT-TD/ATTICA3D that has recently been extended by a fine-mesh diffusion solver. Based on transient analyses for the PBMR-400 design, the transport/diffusion capabilities are demonstrated and 3-D local flux and power redistribution effects during a partial control rod withdrawal are shown. (authors)

  18. Analysis of temporal stability of autostereoscopic 3D displays

    NASA Astrophysics Data System (ADS)

    Rubiño, Manuel; Salas, Carlos; Pozo, Antonio M.; Castro, J. J.; Pérez-Ocón, Francisco

    2013-11-01

    An analysis has been made of the stability of the images generated by electronic autostereoscopic 3D displays, studying the time course of the photometric and colorimetric parameters. The measurements were made on the basis of the procedure recommended in the European guideline EN 61747-6 for the characterization of electronic liquid-crystal displays (LCD). The study uses 3 different models of autostereoscopic 3D displays of different sizes and numbers of pixels, taking the measurements with a spectroradiometer (model PR-670 SpectraScan of PhotoResearch). For each of the displays, the time course is shown for the tristimulus values and the chromaticity coordinates in the XYZ CIE 1931 system and values from the time periods required to reach stable values of these parameters are presented. For the analysis of how the procedure recommended in the guideline EN 61747-6 for 2D displays influenced the results, and for the adaption of the procedure to the characterization of 3D displays, the experimental conditions of the standard procedure were varied, making the stability analysis in the two ocular channels (RE and LE) of the 3D mode and comparing the results with those corresponding to the 2D. The results of our study show that the stabilization time of a autostereoscopic 3D display with parallax barrier technology depends on the tristimulus value analysed (X, Y, Z) as well as on the presentation mode (2D, 3D); furthermore, it was found that whether the 3D mode is used depends on the ocular channel evaluated (RE, LE).

  19. The 3D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Roberts, M. L.; Mcknight, R. L.; Dame, L. T.; Chen, P. C.

    1984-01-01

    Advanced 3-D inelastic structural/stress analysis methods and solution strategies for more accurate and yet more cost-effective analysis of combustors, turbine blades, and vanes are being developed. The approach is to develop four different theories, one linear and three higher order with increasing complexities including embedded singularities. Progress in each area is reported.

  20. Visualization and Analysis of 3D Microscopic Images

    PubMed Central

    Long, Fuhui; Zhou, Jianlong; Peng, Hanchuan

    2012-01-01

    In a wide range of biological studies, it is highly desirable to visualize and analyze three-dimensional (3D) microscopic images. In this primer, we first introduce several major methods for visualizing typical 3D images and related multi-scale, multi-time-point, multi-color data sets. Then, we discuss three key categories of image analysis tasks, namely segmentation, registration, and annotation. We demonstrate how to pipeline these visualization and analysis modules using examples of profiling the single-cell gene-expression of C. elegans and constructing a map of stereotyped neurite tracts in a fruit fly brain. PMID:22719236

  1. Visualization and analysis of 3D microscopic images.

    PubMed

    Long, Fuhui; Zhou, Jianlong; Peng, Hanchuan

    2012-01-01

    In a wide range of biological studies, it is highly desirable to visualize and analyze three-dimensional (3D) microscopic images. In this primer, we first introduce several major methods for visualizing typical 3D images and related multi-scale, multi-time-point, multi-color data sets. Then, we discuss three key categories of image analysis tasks, namely segmentation, registration, and annotation. We demonstrate how to pipeline these visualization and analysis modules using examples of profiling the single-cell gene-expression of C. elegans and constructing a map of stereotyped neurite tracts in a fruit fly brain.

  2. 3D quantitative analysis of brain SPECT images

    NASA Astrophysics Data System (ADS)

    Loncaric, Sven; Ceskovic, Ivan; Petrovic, Ratimir; Loncaric, Srecko

    2001-07-01

    The main purpose of this work is to develop a computer-based technique for quantitative analysis of 3-D brain images obtained by single photon emission computed tomography (SPECT). In particular, the volume and location of ischemic lesion and penumbra is important for early diagnosis and treatment of infracted regions of the brain. SPECT imaging is typically used as diagnostic tool to assess the size and location of the ischemic lesion. The segmentation method presented in this paper utilizes a 3-D deformable model in order to determine size and location of the regions of interest. The evolution of the model is computed using a level-set implementation of the algorithm. In addition to 3-D deformable model the method utilizes edge detection and region growing for realization of a pre-processing. Initial experimental results have shown that the method is useful for SPECT image analysis.

  3. A spherical harmonics intensity model for 3D segmentation and 3D shape analysis of heterochromatin foci.

    PubMed

    Eck, Simon; Wörz, Stefan; Müller-Ott, Katharina; Hahn, Matthias; Biesdorf, Andreas; Schotta, Gunnar; Rippe, Karsten; Rohr, Karl

    2016-08-01

    The genome is partitioned into regions of euchromatin and heterochromatin. The organization of heterochromatin is important for the regulation of cellular processes such as chromosome segregation and gene silencing, and their misregulation is linked to cancer and other diseases. We present a model-based approach for automatic 3D segmentation and 3D shape analysis of heterochromatin foci from 3D confocal light microscopy images. Our approach employs a novel 3D intensity model based on spherical harmonics, which analytically describes the shape and intensities of the foci. The model parameters are determined by fitting the model to the image intensities using least-squares minimization. To characterize the 3D shape of the foci, we exploit the computed spherical harmonics coefficients and determine a shape descriptor. We applied our approach to 3D synthetic image data as well as real 3D static and real 3D time-lapse microscopy images, and compared the performance with that of previous approaches. It turned out that our approach yields accurate 3D segmentation results and performs better than previous approaches. We also show that our approach can be used for quantifying 3D shape differences of heterochromatin foci.

  4. 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.

  5. 3D Network Analysis for Indoor Space Applications

    NASA Astrophysics Data System (ADS)

    Tsiliakou, E.; Dimopoulou, E.

    2016-10-01

    Indoor space differs from outdoor environments, since it is characterized by a higher level of structural complexity, geometry, as well as topological relations. Indoor space can be considered as the most important component in a building's conceptual modelling, on which applications such as indoor navigation, routing or analysis are performed. Therefore, the conceptual meaning of sub spaces or the activities taking place in physical building boundaries (e.g. walls), require the comprehension of the building's indoor hierarchical structure. The scope of this paper is to perform 3D network analysis in a building's interior and is structured as follows: In Section 1 the definition of indoor space is provided and indoor navigation requirements are analysed. Section 2 describes the processes of indoor space modeling, as well as routing applications. In Section 3, a case study is examined involving a 3D building model generated in CityEngine (exterior shell) and ArcScene (interior parts), in which the use of commercially available software tools (ArcGIS, ESRI), in terms of indoor routing and 3D network analysis, are explored. The fundamentals of performing 3D analysis with the ArcGIS Network Analyst extension were tested. Finally a geoprocessing model was presented, which was specifically designed to be used to interactively find the best route in ArcScene. The paper ends with discussion and concluding remarks on Section 4.

  6. 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.

  7. 3-D Experimental Fracture Analysis at High Temperature

    SciTech Connect

    John H. Jackson; Albert S. Kobayashi

    2001-09-14

    T*e, which is an elastic-plastic fracture parameter based on incremental theory of plasticity, was determined numerically and experimentally. The T*e integral of a tunneling crack in 2024-T3 aluminum, three point bend specimen was obtained through a hybrid analysis of moire interferometry and 3-D elastic-plastic finite element analysis. The results were verified by the good agreement between the experimentally and numerically determined T*e on the specimen surface.

  8. A software tool for 3D dose verification and analysis

    NASA Astrophysics Data System (ADS)

    Sa'd, M. Al; Graham, J.; Liney, G. P.

    2013-06-01

    The main recent developments in radiotherapy have focused on improved treatment techniques in order to generate further significant improvements in patient prognosis. There is now an internationally recognised need to improve 3D verification of highly conformal radiotherapy treatments. This is because of the very high dose gradients used in modern treatment techniques, which can result in a small error in the spatial dose distribution leading to a serious complication. In order to gain the full benefits of using 3D dosimetric technologies (such as gel dosimetry), it is vital to use 3D evaluation methods and algorithms. We present in this paper a software solution that provides a comprehensive 3D dose evaluation and analysis. The software is applied to gel dosimetry, which is based on magnetic resonance imaging (MRI) as a read-out method. The software can also be used to compare any two dose distributions, such as two distributions planned using different methods of treatment planning systems, or different dose calculation algorithms.

  9. Receptor dependent multidimensional QSAR for modeling drug--receptor interactions.

    PubMed

    Polanski, Jaroslaw

    2009-01-01

    Quantitative Structure Activity Relationship (QSAR) is an approach of mapping chemical structure to properties. A significant development can be observed in the last two decades in this method which originated from the Hansch analysis based on the logP data and Hammett constant towards a growing importance of the molecular descriptors derived from 3D structure including conformational dynamics and solvation scenarios. However, molecular interactions in biological systems are complex phenomena generating extremely noisy data, if simulated in silico. This decides that activity modeling and predictions are a risky business. Molecular recognition uncertainty in traditional receptor independent (RI) m-QSAR cannot be eliminated but by the inclusion of the receptor data. Modeling ligand-receptor interactions is a complex computational problem. This has limited the development of the receptor dependent (RD) m-QSAR. However, a steady increase of computational power has also improved modeling ability in chemoinformatics and novel RD QSAR methods appeared. Following the RI m-QSAR terminology this is usually classified as RD 3/6D-QSAR. However, a clear systematic m-QSAR classification can be proposed, where dimension m refers to, the static ligand representation (3D), multiple ligand representation (4D), ligand-based virtual or pseudo receptor models (5D), multiple solvation scenarios (6D) and real receptor or target-based receptor model data (7D).

  10. 3D Guided Wave Motion Analysis on Laminated Composites

    NASA Technical Reports Server (NTRS)

    Tian, Zhenhua; Leckey, Cara; Yu, Lingyu

    2013-01-01

    Ultrasonic guided waves have proved useful for structural health monitoring (SHM) and nondestructive evaluation (NDE) due to their ability to propagate long distances with less energy loss compared to bulk waves and due to their sensitivity to small defects in the structure. Analysis of actively transmitted ultrasonic signals has long been used to detect and assess damage. However, there remain many challenging tasks for guided wave based SHM due to the complexity involved with propagating guided waves, especially in the case of composite materials. The multimodal nature of the ultrasonic guided waves complicates the related damage analysis. This paper presents results from parallel 3D elastodynamic finite integration technique (EFIT) simulations used to acquire 3D wave motion in the subject laminated carbon fiber reinforced polymer composites. The acquired 3D wave motion is then analyzed by frequency-wavenumber analysis to study the wave propagation and interaction in the composite laminate. The frequency-wavenumber analysis enables the study of individual modes and visualization of mode conversion. Delamination damage has been incorporated into the EFIT model to generate "damaged" data. The potential for damage detection in laminated composites is discussed in the end.

  11. Visualization and Analysis of 3D Gene Expression Data

    SciTech Connect

    Bethel, E. Wes; Rubel, Oliver; Weber, Gunther H.; Hamann, Bernd; Hagen, Hans

    2007-10-25

    Recent methods for extracting precise measurements ofspatial gene expression patterns from three-dimensional (3D) image dataopens the way for new analysis of the complex gene regulatory networkscontrolling animal development. To support analysis of this novel andhighly complex data we developed PointCloudXplore (PCX), an integratedvisualization framework that supports dedicated multi-modal, physical andinformation visualization views along with algorithms to aid in analyzingthe relationships between gene expression levels. Using PCX, we helpedour science stakeholders to address many questions in 3D gene expressionresearch, e.g., to objectively define spatial pattern boundaries andtemporal profiles of genes and to analyze how mRNA patterns arecontrolled by their regulatory transcription factors.

  12. Advanced computational tools for 3-D seismic analysis

    SciTech Connect

    Barhen, J.; Glover, C.W.; Protopopescu, V.A.

    1996-06-01

    The global objective of this effort is to develop advanced computational tools for 3-D seismic analysis, and test the products using a model dataset developed under the joint aegis of the United States` Society of Exploration Geophysicists (SEG) and the European Association of Exploration Geophysicists (EAEG). The goal is to enhance the value to the oil industry of the SEG/EAEG modeling project, carried out with US Department of Energy (DOE) funding in FY` 93-95. The primary objective of the ORNL Center for Engineering Systems Advanced Research (CESAR) is to spearhead the computational innovations techniques that would enable a revolutionary advance in 3-D seismic analysis. The CESAR effort is carried out in collaboration with world-class domain experts from leading universities, and in close coordination with other national laboratories and oil industry partners.

  13. Advancements in 3D Structural Analysis of Geothermal Systems

    SciTech Connect

    Siler, Drew L; Faulds, James E; Mayhew, Brett; McNamara, David

    2013-06-23

    Robust geothermal activity in the Great Basin, USA is a product of both anomalously high regional heat flow and active fault-controlled extension. Elevated permeability associated with some fault systems provides pathways for circulation of geothermal fluids. Constraining the local-scale 3D geometry of these structures and their roles as fluid flow conduits is crucial in order to mitigate both the costs and risks of geothermal exploration and to identify blind (no surface expression) geothermal resources. Ongoing studies have indicated that much of the robust geothermal activity in the Great Basin is associated with high density faulting at structurally complex fault intersection/interaction areas, such as accommodation/transfer zones between discrete fault systems, step-overs or relay ramps in fault systems, intersection zones between faults with different strikes or different senses of slip, and horse-tailing fault terminations. These conceptualized models are crucial for locating and characterizing geothermal systems in a regional context. At the local scale, however, pinpointing drilling targets and characterizing resource potential within known or probable geothermal areas requires precise 3D characterization of the system. Employing a variety of surface and subsurface data sets, we have conducted detailed 3D geologic analyses of two Great Basin geothermal systems. Using EarthVision (Dynamic Graphics Inc., Alameda, CA) we constructed 3D geologic models of both the actively producing Brady’s geothermal system and a ‘greenfield’ geothermal prospect at Astor Pass, NV. These 3D models allow spatial comparison of disparate data sets in 3D and are the basis for quantitative structural analyses that can aid geothermal resource assessment and be used to pinpoint discrete drilling targets. The relatively abundant data set at Brady’s, ~80 km NE of Reno, NV, includes 24 wells with lithologies interpreted from careful analysis of cuttings and core, a 1

  14. Three-dimensional quantitative structure activity relationship (QSAR) of cytotoxic active 3,5-diaryl-4,5-dihydropyrazole analogs: a comparative molecular field analysis (CoMFA) revisited study

    PubMed Central

    2012-01-01

    In vitro antitumor evaluation of the synthesized 46 compounds of 3,5-diaryl-4,5-dihydropyrazoles against EAC cell lines and 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described. CoMFA derived QSAR model shows a good conventional squared correlation coefficient r2 and cross validated correlation coefficient r2cv 0.896 and 0.568 respectively. In this analysis steric and electrostatic field contribute to the QSAR equation by 70% and 30% respectively, suggesting that variation in biological activity of the compounds is dominated by differences in steric (van der Waals) interactions. To visualize the CoMFA steric and electrostatic field from partial least squares (PLS) analysis, contour maps are plotted as percentage contribution to the QSAR equation and are associated with the differences in biological activity. Background Pyrazole derivatives exhibit a wide range of biological properties including promising antitumor activity. Furthermore, Aldol condensation assisted organic synthesis has delivered rapid routes to N-containing heterocycles, including pyrazoles. Combining these features, the use of chalconisation-assisted processes will provide rapid access to a targeted dihydropyrazoles library bearing a hydrazino 3D QSAR study using pharmacophore and Comparative Molecular Field Analysis (CoMFA) methods were described for evaluation of antioxidant properties. Results Chalcones promoted 1 of the 2 steps in a rapid, convergent synthesis of a small library of hydrazinyl pyrazole derivatives, all of which exhibited significant antitumor activity against Ehrlich Ascites Carcinoma (EAC) human tumor cell line comparable to that of the natural anticancer doxorubicin, as a reference standard during this study. In order to understand the observed pharmacological properties, quantitative structure-activity relationship (3D QSAR) study was initiated. Conclusions Chalcones heating provides a rapid and expedient route to a series

  15. 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.

  16. Beam Optics Analysis - An Advanced 3D Trajectory Code

    SciTech Connect

    Ives, R. Lawrence; Bui, Thuc; Vogler, William; Neilson, Jeff; Read, Mike; Shephard, Mark; Bauer, Andrew; Datta, Dibyendu; Beal, Mark

    2006-01-03

    Calabazas Creek Research, Inc. has completed initial development of an advanced, 3D program for modeling electron trajectories in electromagnetic fields. The code is being used to design complex guns and collectors. Beam Optics Analysis (BOA) is a fully relativistic, charged particle code using adaptive, finite element meshing. Geometrical input is imported from CAD programs generating ACIS-formatted files. Parametric data is inputted using an intuitive, graphical user interface (GUI), which also provides control of convergence, accuracy, and post processing. The program includes a magnetic field solver, and magnetic information can be imported from Maxwell 2D/3D and other programs. The program supports thermionic emission and injected beams. Secondary electron emission is also supported, including multiple generations. Work on field emission is in progress as well as implementation of computer optimization of both the geometry and operating parameters. The principle features of the program and its capabilities are presented.

  17. Interactive color display of 3-D engineering analysis results

    NASA Technical Reports Server (NTRS)

    Abel, John F.; Ingraffea, Anthony R.; Greenberg, Donald P.

    1987-01-01

    A general approach to three-dimensional postprocessing of engineering analyses is presented. The approach is versatile and may handle the results from a wide range of engineering analysis methods which involve the discretization of continua. To facilitate the understanding of complex three-dimensional numerical models, advanced interactive color postprocessing techniques are introduced. Finite element, finite difference, and boundary element models are evaluated with the prototype postprocessor. The existing color graphics program (POSTPRO3D) was ported to a high-resolution device. Interactive graphic tools were implemented to facilitate qualitative mesh evaluation from a single analysis. A postprocessing environment was design for workstation technology.

  18. Uncertainty Analysis for RELAP5-3D

    SciTech Connect

    Aaron J. Pawel; Dr. George L. Mesina

    2011-08-01

    In its current state, RELAP5-3D is a 'best-estimate' code; it is one of our most reliable programs for modeling what occurs within reactor systems in transients from given initial conditions. This code, however, remains an estimator. A statistical analysis has been performed that begins to lay the foundation for a full uncertainty analysis. By varying the inputs over assumed probability density functions, the output parameters were shown to vary. Using such statistical tools as means, variances, and tolerance intervals, a picture of how uncertain the results are based on the uncertainty of the inputs has been obtained.

  19. Breast tumor angiogenesis analysis using 3D power Doppler ultrasound

    NASA Astrophysics Data System (ADS)

    Chang, Ruey-Feng; Huang, Sheng-Fang; Lee, Yu-Hau; Chen, Dar-Ren; Moon, Woo Kyung

    2006-03-01

    Angiogenesis is the process that correlates to tumor growth, invasion, and metastasis. Breast cancer angiogenesis has been the most extensively studied and now serves as a paradigm for understanding the biology of angiogenesis and its effects on tumor outcome and patient prognosis. Most studies on characterization of angiogenesis focus on pixel/voxel counts more than morphological analysis. Nevertheless, in cancer, the blood flow is greatly affected by the morphological changes, such as the number of vessels, branching pattern, length, and diameter. This paper presents a computer-aided diagnostic (CAD) system that can quantify vascular morphology using 3-D power Doppler ultrasound (US) on breast tumors. We propose a scheme to extract the morphological information from angiography and to relate them to tumor diagnosis outcome. At first, a 3-D thinning algorithm helps narrow down the vessels into their skeletons. The measurements of vascular morphology significantly rely on the traversing of the vascular trees produced from skeletons. Our study of 3-D assessment of vascular morphological features regards vessel count, length, bifurcation, and diameter of vessels. Investigations into 221 solid breast tumors including 110 benign and 111 malignant cases, the p values using the Student's t-test for all features are less than 0.05 indicating that the proposed features are deemed statistically significant. Our scheme focuses on the vascular architecture without involving the technique of tumor segmentation. The results show that the proposed method is feasible, and have a good agreement with the diagnosis of the pathologists.

  20. USM3D Analysis of Low Boom Configuration

    NASA Technical Reports Server (NTRS)

    Carter, Melissa B.; Campbell, Richard L.; Nayani, Sudheer N.

    2011-01-01

    In the past few years considerable improvement was made in NASA's in house boom prediction capability. As part of this improved capability, the USM3D Navier-Stokes flow solver, when combined with a suitable unstructured grid, went from accurately predicting boom signatures at 1 body length to 10 body lengths. Since that time, the research emphasis has shifted from analysis to the design of supersonic configurations with boom signature mitigation In order to design an aircraft, the techniques for accurately predicting boom and drag need to be determined. This paper compares CFD results with the wind tunnel experimental results conducted on a Gulfstream reduced boom and drag configuration. Two different wind-tunnel models were designed and tested for drag and boom data. The goal of this study was to assess USM3D capability for predicting both boom and drag characteristics. Overall, USM3D coupled with a grid that was sheared and stretched was able to reasonably predict boom signature. The computational drag polar matched the experimental results for a lift coefficient above 0.1 despite some mismatch in the predicted lift-curve slope.

  1. Computerized 3D morphological analysis of glenoid orientation.

    PubMed

    Ghafurian, Soheil; Galdi, Balazs; Bastian, Sevag; Tan, Virak; Li, Kang

    2016-04-01

    An accurate preoperative measurement of glenoid orientation is crucial for evaluating pathologies and successful total shoulder arthroplasty. Existing methods may be labor-intensive, observer-dependent, and sensitive to the misalignment between the scapula plane and CT scanning direction. In this study, we proposed a computation framework and performed an automated analysis of the glenoid orientation based on 3D surface data. Three-dimensional models of 12 scapulae were analyzed. The glenoid cavity and external anatomical features were automatically extracted from these 3D models. Glenoid version was calculated using the scapula plane and the fulcrum axis alternatively. Glenoid inclination was measured both relative to transverse axis of the scapula and the medial pole-inferior tip axis. The mean (±SD) of the fulcrum-based glenoid version was -0.55° (±4.17°), while the scapular-plane-based glenoid version was -5.05° (±3.50°). The mean (±SD) of glenoid inclinations based on the medial pole and inferior tip was 12.75° (±5.03°) while the mean (±SD) of the glenoid inclination based on the medial pole and glenoid center was 4.63° (±4.86°). Our computational framework was able to extract the reproducible morphological measures free of inter- and intra- observer variability. For the first time in 3D, we showed that the fulcrum axis was practically perpendicular to the glenoid plane normal (radial line), and thus extended the fulcrum-based glenoid version for quantifying 3D glenoid orientation. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  2. Optical 3D shape, surface, and material analysis

    NASA Astrophysics Data System (ADS)

    Tiziani, Hans J.

    2001-06-01

    Different techniques are available for macro- and micro- topometry. The methods are basically known but their industrial implementation requires robust measuring systems, where calibration is an important necessity. Different techniques will be presented. New elements such as liquid crystal displays and micromirror devices are available leading to new applications to be discussed. Combinative methods and integration in measuring systems becomes interesting. The state of the art and new developments will be presented. Together with calibration for 3D-shock or vibration analysis an object shape measuring systems will be directly combined with a vibration measuring system.

  3. The 3D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Mcknight, R. L.; Maffeo, R. J.; Tipton, M. T.; Weber, G.

    1992-01-01

    A two-year program to develop advanced 3D inelastic structural stress analysis methods and solution strategies for more accurate and cost effective analysis of combustors, turbine blades, and vanes is described. The approach was to develop a matrix of formulation elements and constitutive models. Three constitutive models were developed in conjunction with optimized iterating techniques, accelerators, and convergence criteria within a framework of dynamic time incrementing. Three formulation models were developed: an eight-noded midsurface shell element; a nine-noded midsurface shell element; and a twenty-noded isoparametric solid element. A separate computer program has been developed for each combination of constitutive model-formulation model. Each program provides a functional stand alone capability for performing cyclic nonlinear structural analysis. In addition, the analysis capabilities incorporated into each program can be abstracted in subroutine form for incorporation into other codes or to form new combinations.

  4. On 3D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Mcknight, R. L.; Chen, P. C.; Dame, L. T.; Holt, R. V.; Huang, H.; Hartle, M.; Gellin, S.; Allen, D. H.; Haisler, W. E.

    1986-01-01

    Accomplishments are described for the 2-year program, to develop advanced 3-D inelastic structural stress analysis methods and solution strategies for more accurate and cost effective analysis of combustors, turbine blades and vanes. The approach was to develop a matrix of formulation elements and constitutive models. Three constitutive models were developed in conjunction with optimized iterating techniques, accelerators, and convergence criteria within a framework of dynamic time incrementing. Three formulations models were developed; an eight-noded mid-surface shell element, a nine-noded mid-surface shell element and a twenty-noded isoparametric solid element. A separate computer program was developed for each combination of constitutive model-formulation model. Each program provides a functional stand alone capability for performing cyclic nonlinear structural analysis. In addition, the analysis capabilities incorporated into each program can be abstracted in subroutine form for incorporation into other codes or to form new combinations.

  5. Development of 3D Slicer based film dosimetry analysis

    NASA Astrophysics Data System (ADS)

    Alexander, K. M.; Robinson, A.; Pinter, C.; Fichtinger, G.; Schreiner, L. J.

    2017-05-01

    Radiochromic film dosimetry has been widely adopted in the clinic as it is a convenient option for dose measurement and verification. Film dosimetry analysis is typically performed using expensive commercial software, or custom made scripts in Matlab. However, common clinical film analysis software is not transparent regarding what corrections/optimizations are running behind the scenes. In this work, an extension to the open-source medical imaging platform 3D Slicer was developed and implemented in our centre for film dosimetry analysis. This extension streamlines importing treatment planning system dose and film imaging data, film calibration, registration, and comparison of 2D dose distributions, enabling greater accessibility to film analysis and higher reliability.

  6. The development of a 3D risk analysis method.

    PubMed

    I, Yet-Pole; Cheng, Te-Lung

    2008-05-01

    Much attention has been paid to the quantitative risk analysis (QRA) research in recent years due to more and more severe disasters that have happened in the process industries. Owing to its calculation complexity, very few software, such as SAFETI, can really make the risk presentation meet the practice requirements. However, the traditional risk presentation method, like the individual risk contour in SAFETI, is mainly based on the consequence analysis results of dispersion modeling, which usually assumes that the vapor cloud disperses over a constant ground roughness on a flat terrain with no obstructions and concentration fluctuations, which is quite different from the real situations of a chemical process plant. All these models usually over-predict the hazardous regions in order to maintain their conservativeness, which also increases the uncertainty of the simulation results. On the other hand, a more rigorous model such as the computational fluid dynamics (CFD) model can resolve the previous limitations; however, it cannot resolve the complexity of risk calculations. In this research, a conceptual three-dimensional (3D) risk calculation method was proposed via the combination of results of a series of CFD simulations with some post-processing procedures to obtain the 3D individual risk iso-surfaces. It is believed that such technique will not only be limited to risk analysis at ground level, but also be extended into aerial, submarine, or space risk analyses in the near future.

  7. Somatotyping using 3D anthropometry: a cluster analysis.

    PubMed

    Olds, Tim; Daniell, Nathan; Petkov, John; David Stewart, Arthur

    2013-01-01

    Somatotyping is the quantification of human body shape, independent of body size. Hitherto, somatotyping (including the most popular method, the Heath-Carter system) has been based on subjective visual ratings, sometimes supported by surface anthropometry. This study used data derived from three-dimensional (3D) whole-body scans as inputs for cluster analysis to objectively derive clusters of similar body shapes. Twenty-nine dimensions normalised for body size were measured on a purposive sample of 301 adults aged 17-56 years who had been scanned using a Vitus Smart laser scanner. K-means Cluster Analysis with v-fold cross-validation was used to determine shape clusters. Three male and three female clusters emerged, and were visualised using those scans closest to the cluster centroid and a caricature defined by doubling the difference between the average scan and the cluster centroid. The male clusters were decidedly endomorphic (high fatness), ectomorphic (high linearity), and endo-mesomorphic (a mixture of fatness and muscularity). The female clusters were clearly endomorphic, ectomorphic, and the ecto-mesomorphic (a mixture of linearity and muscularity). An objective shape quantification procedure combining 3D scanning and cluster analysis yielded shape clusters strikingly similar to traditional somatotyping.

  8. 3D morphometric analysis of human fetal cerebellar development.

    PubMed

    Scott, Julia A; Hamzelou, Kia S; Rajagopalan, Vidya; Habas, Piotr A; Kim, Kio; Barkovich, A James; Glenn, Orit A; Studholme, Colin

    2012-09-01

    To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R (2) = 0.96) compared to the linear curve (R (2) = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R (2) = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R (2) = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure.

  9. 3D Morphometric Analysis of Human Fetal Cerebellar Development

    PubMed Central

    Hamzelou, Kia S.; Rajagopalan, Vidya; Habas, Piotr A.; Kim, Kio; Barkovich, A. James; Glenn, Orit A.; Studholme, Colin

    2012-01-01

    To date, growth of the human fetal cerebellum has been estimated primarily from linear measurements from ultrasound and 2D magnetic resonance imaging (MRI). In this study, we use 3D analytical methods to develop normative growth trajectories for the cerebellum in utero. We measured cerebellar volume, linear dimensions, and local surface curvature from 3D reconstructed MRI of the human fetal brain (N = 46). We found that cerebellar volume increased approximately 7-fold from 20 to 31 gestational weeks. The better fit of the exponential curve (R2 = 0.96) compared to the linear curve (R2 = 0.92) indicated acceleration in growth. Within-subject cerebellar and cerebral volumes were highly correlated (R2 = 0.94), though the cerebellar percentage of total brain volume increased from approximately 2.4% to 3.7% (R2 = 0.63). Right and left hemispheric volumes did not significantly differ. Transcerebellar diameter, vermal height, and vermal anterior to posterior diameter increased significantly at constant rates. From the local curvature analysis, we found that expansion along the inferior and superior aspects of the hemispheres resulted in decreased convexity, which is likely due to the physical constraints of the dura surrounding the cerebellum and the adjacent brainstem. The paired decrease in convexity along the inferior vermis and increased convexity of the medial hemisphere represents development of the paravermian fissure, which becomes more visible during this period. In this 3D morphometric analysis of the human fetal cerebellum, we have shown that cerebellar growth is accelerating at a greater pace than the cerebrum and described how cerebellar growth impacts the shape of the structure. PMID:22198870

  10. Computational analysis of flow in 3D propulsive transition ducts

    NASA Technical Reports Server (NTRS)

    Sepri, Paavo

    1990-01-01

    A numerical analysis of fully three dimensional, statistically steady flows in propulsive transition ducts being considered for use in future aircraft of higher maneuverability is investigated. The purpose of the transition duct is to convert axisymmetric flow from conventional propulsion systems to that of a rectangular geometry of high aspect ratio. In an optimal design, the transition duct would be of minimal length in order to reduce the weight penalty, while the geometrical change would be gradual enough to avoid detrimental flow perturbations. Recent experiments conducted at the Propulsion Aerodynamics Branch have indicated that thrust losses in ducts of superelliptic cross-section can be surprisingly low, even if flow separation occurs near the divergent walls. In order to address the objective of developing a rational design procedure for optimal transition ducts, it is necessary to have available a reliable computational tool for the analysis of flows achieved in a sequence of configurations. Current CFD efforts involving complicated geometries usually must contend with two separate but interactive aspects: namely, grid generation and flow solution. The first two avenues of the present investigation were comprised of suitable grid generation for a class of transition ducts of superelliptic cross-section, and the subsequent application of the flow solver PAB3D to this geometry. The code, PAB3D, was developed as a comprehensive tool for the solution of both internal and external high speed flows. The third avenue of investigation has involved analytical formulations to aid in the understanding of the nature of duct flows, and also to provide a basis of comparison for subsequent numerical solutions. Numerical results to date include the generation of two preliminary grid systems for duct flows, and the initial application of PAB3D to the corresponding geometries, which are of the class tested experimentally.

  11. Uncertainty Analysis of RELAP5-3D

    SciTech Connect

    Alexandra E Gertman; Dr. George L Mesina

    2012-07-01

    As world-wide energy consumption continues to increase, so does the demand for the use of alternative energy sources, such as Nuclear Energy. Nuclear Power Plants currently supply over 370 gigawatts of electricity, and more than 60 new nuclear reactors have been commissioned by 15 different countries. The primary concern for Nuclear Power Plant operation and lisencing has been safety. The safety of the operation of Nuclear Power Plants is no simple matter- it involves the training of operators, design of the reactor, as well as equipment and design upgrades throughout the lifetime of the reactor, etc. To safely design, operate, and understand nuclear power plants, industry and government alike have relied upon the use of best-estimate simulation codes, which allow for an accurate model of any given plant to be created with well-defined margins of safety. The most widely used of these best-estimate simulation codes in the Nuclear Power industry is RELAP5-3D. Our project focused on improving the modeling capabilities of RELAP5-3D by developing uncertainty estimates for its calculations. This work involved analyzing high, medium, and low ranked phenomena from an INL PIRT on a small break Loss-Of-Coolant Accident as wall as an analysis of a large break Loss-Of- Coolant Accident. Statistical analyses were performed using correlation coefficients. To perform the studies, computer programs were written that modify a template RELAP5 input deck to produce one deck for each combination of key input parameters. Python scripting enabled the running of the generated input files with RELAP5-3D on INL’s massively parallel cluster system. Data from the studies was collected and analyzed with SAS. A summary of the results of our studies are presented.

  12. Approach to 3d Analysis of Gravity Ptosis

    NASA Astrophysics Data System (ADS)

    Guryanov, R. A.; Monkin, S.; Monkin, A.; Petrov, A.

    2017-05-01

    The assessment of ptosis degree for rejuvenation procedures, the choice of following operation technique and evaluation of surgery result are based on subjective visual examination and surgeon's experience. The photogrammetric scans of 25 female patients of age 20 to 55 in vertical and supine (horizontal) position of body with placing the regular marker points on the face were analyzed. For 5 patients, also the CT data was acquired and segmentation of soft tissue was performed. Four of these patients underwent SMAS-lifting, the photogrammetry scanning was repeat 6 months after the operation. Computer vision algorithms was used for markers detection on the 3D model texture, marker were projected from texture to triangular mesh. 3D mesh models were registered with user defined anatomy points and pair selection based on markers location was done. Pairs of points on vertical and horizontal 3D models were analyzed for surface tissue mobility examination. The migration vectors of each side of the face are uniformly directed upwards and laterally. The vectors are projected at the areas of so-called ligaments demonstrate no evidence in deviation from row sequences. The volume migration is strongly correlates with the age of examined patients, on the contrary the point migration moderately correlates with age in patients of 30 to 50 years old. The analysis of migration vectors before and after the SMAS-lifting revealed no significant changes in surface points' migration. The described method allows to assess the mechanical conditions of individual face and evaluate efficacy of surgery. This approach can be used for the classification of face ptosis grade.

  13. Triangulation Based 3D Laser Imaging for Fracture Orientation Analysis

    NASA Astrophysics Data System (ADS)

    Mah, J.; Claire, S.; Steve, M.

    2009-05-01

    sets (strike/dip: 060/00, 114/86) were identified from 49 manual inclinometer measurements A stereonet of joint poles from the 3D laser data was generated using the commercial software Split-FX. Joint sets were identified successfully and their orientations correlated well with the hand measurements. However, Split-Fx overlays a simply 2D grid of equal-sized triangles onto the 3D surface and requires significant user input. In a more automated approach, we have developed a MATLAB script which directly imports the Polyworks 3D triangular mesh. A typical mesh is composed of over 1 million triangles of variable sizes: smooth regions are represented by large triangles, whereas rough surfaces are captured by several smaller triangles. Using the triangle vertices, the script computes the strike and dip of each triangle. This approach opens possibilities for statistical analysis of a large population of fracture orientation estimates, including surface texture. The methodology will be used to evaluate both synthetic and field data.

  14. Grid-based continual analysis of molecular interior for drug discovery, QSAR and QSPR.

    PubMed

    Potemkin, A V; Grishina, M A; Potemkin, V A

    2017-02-07

    In 1979, R.D.Cramer and M.Milne made a first realization of the above mentioned principles attempting to compare molecules by aligning them in space and by mapping their molecular fields to a 3D grid. Further, this approach was developed as the DYLOMMS (DYnamic Lattice-Oriented Molecular Modelling System) approach. In 1984, H.Wold and S.Wold proposed the use of partial least squares (PLS) analysis, instead of principal component analysis, to correlate the field values with biological activities. Then, in 1988 the method which was called CoMFA (Comparative Molecular Field Analysis) was introduced and the appropriate software became commercially available. Since 1988, a lot of 3D QSAR methods, algorithms and their modifications are introduced for solving of virtual drug discovery problems (e.g., CoMSIA, CoMMA, HINT, HASL, GOLPE, GRID, PARM, Raptor, BiS, CiS, ConGO,). All the methods can be divided into two groups (classes):1. Methods studying the exterior of molecules; 2) Methods studying the interior of molecules. A series of grid-based computational technologies for Continual Molecular Interior analysis (CoMIn) is invented in the current paper. The grid-based analysis is fulfilled by means of a lattice construction analogously to many other grid-based methods. The further continual elucidation of molecular structure is performed in various ways. (i) In the terms of intermolecular interactions potentials. This can be represented as a superposition of Coulomb, Van der Waals interactions and hydrogen bonds. All the potentials are well known continual functions and their values can be determined in all lattice points for a molecule. (ii) In the terms of quantum functions such as electron density distribution, Laplacian and Hamiltonian of electron density distribution, potential energy distribution, the highest occupied and the lowest unoccupied molecular orbitals distribution and their superposition. To reduce time of calculations using quantum methods based on the

  15. The 3D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Dame, L. T.; Mcknight, R. L.

    1983-01-01

    The objective of this research is to develop an analytical tool capable of economically evaluating the cyclic time dependent plasticity which occurs in hot section engine components in areas of strain concentration resulting from the combination of both mechanical and thermal stresses. The techniques developed must be capable of accommodating large excursions in temperatures with the associated variations in material properties including plasticity and creep. The overall objective of this proposed program is to develop advanced 3-D inelastic structural/stress analysis methods and solution strategies for more accurate and yet more cost effective analysis of combustors, turbine blades, and vanes. The approach will be to develop four different theories, one linear and three higher order with increasing complexities including embedded singularities.

  16. Dynamical Systems Analysis of Fully 3D Ocean Features

    NASA Astrophysics Data System (ADS)

    Pratt, L. J.

    2011-12-01

    Dynamical systems analysis of transport and stirring processes has been developed most thoroughly for 2D flow fields. The calculation of manifolds, turnstile lobes, transport barriers, etc. based on observations of the ocean is most often conducted near the sea surface, whereas analyses at depth, usually carried out with model output, is normally confined to constant-z surfaces. At the meoscale and larger, ocean flows are quasi 2D, but smaller scale (submesoscale) motions, including mixed layer phenomena with significant vertical velocity, may be predominantly 3D. The zoology of hyperbolic trajectories becomes richer in such cases and their attendant manifolds are much more difficult to calculate. I will describe some of the basic geometrical features and corresponding Lagrangian Coherent Features expected to arise in upper ocean fronts, eddies, and Langmuir circulations. Traditional GFD models such as the rotating can flow may capture the important generic features. The dynamical systems approach is most helpful when these features are coherent and persistent and the implications and difficulties for this requirement in fully 3D flows will also be discussed.

  17. Comparative visual analysis of 3D urban wind simulations

    NASA Astrophysics Data System (ADS)

    Röber, Niklas; Salim, Mohamed; Grawe, David; Leitl, Bernd; Böttinger, Michael; Schlünzen, Heinke

    2016-04-01

    Climate simulations are conducted in large quantity for a variety of different applications. Many of these simulations focus on global developments and study the Earth's climate system using a coupled atmosphere ocean model. Other simulations are performed on much smaller regional scales, to study very small fine grained climatic effects. These microscale climate simulations pose similar, yet also different, challenges for the visualization and the analysis of the simulation data. Modern interactive visualization and data analysis techniques are very powerful tools to assist the researcher in answering and communicating complex research questions. This presentation discusses comparative visualization for several different wind simulations, which were created using the microscale climate model MITRAS. The simulations differ in wind direction and speed, but are all centered on the same simulation domain: An area of Hamburg-Wilhelmsburg that hosted the IGA/IBA exhibition in 2013. The experiments contain a scenario case to analyze the effects of single buildings, as well as examine the impact of the Coriolis force within the simulation. The scenario case is additionally compared with real measurements from a wind tunnel experiment to ascertain the accuracy of the simulation and the model itself. We also compare different approaches for tree modeling and evaluate the stability of the model. In this presentation, we describe not only our workflow to efficiently and effectively visualize microscale climate simulation data using common 3D visualization and data analysis techniques, but also discuss how to compare variations of a simulation and how to highlight the subtle differences in between them. For the visualizations we use a range of different 3D tools that feature techniques for statistical data analysis, data selection, as well as linking and brushing.

  18. Automated 3-D analysis of Gravity Dam stability

    SciTech Connect

    Barrett, P.R.; Boggs, H.

    1995-12-31

    The safety and stability of nonfederal hydroelectric project dams in the U.S. is a responsibility of the Federal Energy Regulatory Commission (FERC). FERC requires dam owners to reevaluate their structure`s stability every five years. In spite of the fact that FERC guidelines allow owners to use a variety of analytical approaches, millions of dollars are spent each year on safety modifications based on sometimes very conservative analysis methods. Analysis methods are often limited to hand calculations that assume a 2-D rigid body bending response of the dam or automated 2-D finite element analyses which can sometimes predict smaller safety factors than the rigid body analyses. Evaluation of dam stability using 3-D finite element analyses can sometimes reduce the conservatism in evaluating a dam`s stability even when conventional wisdom suggests that a 2-D analysis is sufficient. Significant increases in stability obtained from the 3-D analyses come primarily from the confining stresses from the dam abutments and the redistribution of load along the dam`s length. Even when the confining stresses are relatively small, large changes in sliding safety factors can be seen, since most dams, stability is extremely sensitive to variations in dam-rock interface cracks. The confining stresses reduce the propagation of cracks. The length of crack controls the magnitude of uplift loads applied to the bottom of the dam which in turn potentially leads to longer crack lengths. Both crack length and magnitude of uplift load directly effect the sliding stability factor of safety.

  19. Colossal Tooling Design: 3D Simulation for Ergonomic Analysis

    NASA Technical Reports Server (NTRS)

    Hunter, Steve L.; Dischinger, Charles; Thomas, Robert E.; Babai, Majid

    2003-01-01

    The application of high-level 3D simulation software to the design phase of colossal mandrel tooling for composite aerospace fuel tanks was accomplished to discover and resolve safety and human engineering problems. The analyses were conducted to determine safety, ergonomic and human engineering aspects of the disassembly process of the fuel tank composite shell mandrel. Three-dimensional graphics high-level software, incorporating various ergonomic analysis algorithms, was utilized to determine if the process was within safety and health boundaries for the workers carrying out these tasks. In addition, the graphical software was extremely helpful in the identification of material handling equipment and devices for the mandrel tooling assembly/disassembly process.

  20. Discovery of potent and selective urea-based ROCK inhibitors: Exploring the inhibitor's potency and ROCK2/PKA selectivity by 3D-QSAR, molecular docking and molecular dynamics simulations.

    PubMed

    Mei, Ding; Yin, Yan; Wu, Fanhong; Cui, Jiaxing; Zhou, Hong; Sun, Guofeng; Jiang, Yu; Feng, Yangbo

    2015-05-15

    An activity model and a selectivity model from 3D-QSAR studies were established by CoMFA and CoMSIA to explore the SAR. Then docking was used to study the binding modes between ligand and kinases (ROCK2 and PKA), and the molecular docking results were further validated by MD simulations. Computational results suggested that substitution containing positive charge attached to the middle phenyl ring, or electropositive group in urea linker was favored for both activity and ROCK2/PKA selectivity. Finally, three compounds were designed, and biological evaluation demonstrated that these molecular models were effective for guiding the design of potent and selective ROCK inhibitors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Quantitative 3D analysis of huge nanoparticle assemblies

    NASA Astrophysics Data System (ADS)

    Zanaga, Daniele; Bleichrodt, Folkert; Altantzis, Thomas; Winckelmans, Naomi; Palenstijn, Willem Jan; Sijbers, Jan; de Nijs, Bart; van Huis, Marijn A.; Sánchez-Iglesias, Ana; Liz-Marzán, Luis M.; van Blaaderen, Alfons; Joost Batenburg, K.; Bals, Sara; van Tendeloo, Gustaaf

    2015-12-01

    Nanoparticle assemblies can be investigated in 3 dimensions using electron tomography. However, it is not straightforward to obtain quantitative information such as the number of particles or their relative position. This becomes particularly difficult when the number of particles increases. We propose a novel approach in which prior information on the shape of the individual particles is exploited. It improves the quality of the reconstruction of these complex assemblies significantly. Moreover, this quantitative Sparse Sphere Reconstruction approach yields directly the number of particles and their position as an output of the reconstruction technique, enabling a detailed 3D analysis of assemblies with as many as 10 000 particles. The approach can also be used to reconstruct objects based on a very limited number of projections, which opens up possibilities to investigate beam sensitive assemblies where previous reconstructions with the available electron tomography techniques failed.Nanoparticle assemblies can be investigated in 3 dimensions using electron tomography. However, it is not straightforward to obtain quantitative information such as the number of particles or their relative position. This becomes particularly difficult when the number of particles increases. We propose a novel approach in which prior information on the shape of the individual particles is exploited. It improves the quality of the reconstruction of these complex assemblies significantly. Moreover, this quantitative Sparse Sphere Reconstruction approach yields directly the number of particles and their position as an output of the reconstruction technique, enabling a detailed 3D analysis of assemblies with as many as 10 000 particles. The approach can also be used to reconstruct objects based on a very limited number of projections, which opens up possibilities to investigate beam sensitive assemblies where previous reconstructions with the available electron tomography techniques

  2. 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.

  3. 3D Material Response Analysis of PICA Pyrolysis Experiments

    NASA Technical Reports Server (NTRS)

    Oliver, A. Brandon

    2017-01-01

    The PICA decomposition experiments of Bessire and Minton are investigated using 3D material response analysis. The steady thermoelectric equations have been added to the CHAR code to enable analysis of the Joule-heated experiments and the DAKOTA optimization code is used to define the voltage boundary condition that yields the experimentally observed temperature response. This analysis has identified a potential spatial non-uniformity in the PICA sample temperature driven by the cooled copper electrodes and thermal radiation from the surface of the test article (Figure 1). The non-uniformity leads to a variable heating rate throughout the sample volume that has an effect on the quantitative results of the experiment. Averaging the results of integrating a kinetic reaction mechanism with the heating rates seen across the sample volume yield a shift of peak species production to lower temperatures that is more significant for higher heating rates (Figure 2) when compared to integrating the same mechanism at the reported heating rate. The analysis supporting these conclusions will be presented along with a proposed analysis procedure that permits quantitative use of the existing data. Time permitting, a status on the in-development kinetic decomposition mechanism based on this data will be presented as well.

  4. 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

  5. 3D Image Analysis of Geomaterials using Confocal Microscopy

    NASA Astrophysics Data System (ADS)

    Mulukutla, G.; Proussevitch, A.; Sahagian, D.

    2009-05-01

    Confocal microscopy is one of the most significant advances in optical microscopy of the last century. It is widely used in biological sciences but its application to geomaterials lingers due to a number of technical problems. Potentially the technique can perform non-invasive testing on a laser illuminated sample that fluoresces using a unique optical sectioning capability that rejects out-of-focus light reaching the confocal aperture. Fluorescence in geomaterials is commonly induced using epoxy doped with a fluorochrome that is impregnated into the sample to enable discrimination of various features such as void space or material boundaries. However, for many geomaterials, this method cannot be used because they do not naturally fluoresce and because epoxy cannot be impregnated into inaccessible parts of the sample due to lack of permeability. As a result, the confocal images of most geomaterials that have not been pre-processed with extensive sample preparation techniques are of poor quality and lack the necessary image and edge contrast necessary to apply any commonly used segmentation techniques to conduct any quantitative study of its features such as vesicularity, internal structure, etc. In our present work, we are developing a methodology to conduct a quantitative 3D analysis of images of geomaterials collected using a confocal microscope with minimal amount of prior sample preparation and no addition of fluorescence. Two sample geomaterials, a volcanic melt sample and a crystal chip containing fluid inclusions are used to assess the feasibility of the method. A step-by-step process of image analysis includes application of image filtration to enhance the edges or material interfaces and is based on two segmentation techniques: geodesic active contours and region competition. Both techniques have been applied extensively to the analysis of medical MRI images to segment anatomical structures. Preliminary analysis suggests that there is distortion in the

  6. Structural analysis of tropical cyclone using INSAT-3D observations

    NASA Astrophysics Data System (ADS)

    Jaiswal, Neeru; Kishtawal, C. M.

    2016-05-01

    The continuous observations from visible and thermal infrared (TIR) channels of geostationary satellites are highly useful for obtaining the features associated with the shape and dynamics of cloud structures within the tropical cyclones (TCs). As TC develops from an unstructured cloud cluster and intensifies, the cloud structures become more axisymmetric around the centre of the TC. To better understand the structure of TC during different stages of its evolution i.e. from its cyclogenesis to maturity and dissipation, the continuous satellite observations plays a key role. The high spatial and temporal resolution observations from geostationary satellites are very useful in order to analyze the cloud organization during the cyclogenesis. The gradient of the brightness temperatures measures the level of symmetry of each structure, which characterizes the degree of cloud organization of the TC. In the present work, the structural analysis of TC during its life period using the observations from Indian geostationary satellite INSAT-3D has been discussed. The visible and TIR observations from INSAT-3D satellite were used to fix the center position of the cyclone which is an input for the cyclone track and intensity prediction models. This data is also used to estimate the intensity of cyclone in the advanced Dvorak technique (ADT), and in the estimation of radius of maximum winds (Rmax) of TC which is an essential input parameter for the prediction of storm surge associated to the cyclones. The different patterns of cloud structure during the intensification stage, eye-wall formation and dissipation have been discussed. The early identification of these features helps in predicting the rapid intensification of TC which in turn improves the intensity predictions.

  7. Bioprinted 3D vascularized tissue model for drug toxicity analysis.

    PubMed

    Massa, Solange; Sakr, Mahmoud Ahmed; Seo, Jungmok; Bandaru, Praveen; Arneri, Andrea; Bersini, Simone; Zare-Eelanjegh, Elaheh; Jalilian, Elmira; Cha, Byung-Hyun; Antona, Silvia; Enrico, Alessandro; Gao, Yuan; Hassan, Shabir; Acevedo, Juan Pablo; Dokmeci, Mehmet R; Zhang, Yu Shrike; Khademhosseini, Ali; Shin, Su Ryon

    2017-07-01

    To develop biomimetic three-dimensional (3D) tissue constructs for drug screening and biological studies, engineered blood vessels should be integrated into the constructs to mimic the drug administration process in vivo. The development of perfusable vascularized 3D tissue constructs for studying the drug administration process through an engineered endothelial layer remains an area of intensive research. Here, we report the development of a simple 3D vascularized liver tissue model to study drug toxicity through the incorporation of an engineered endothelial layer. Using a sacrificial bioprinting technique, a hollow microchannel was successfully fabricated in the 3D liver tissue construct created with HepG2/C3A cells encapsulated in a gelatin methacryloyl hydrogel. After seeding human umbilical vein endothelial cells (HUVECs) into the microchannel, we obtained a vascularized tissue construct containing a uniformly coated HUVEC layer within the hollow microchannel. The inclusion of the HUVEC layer into the scaffold resulted in delayed permeability of biomolecules into the 3D liver construct. In addition, the vascularized construct containing the HUVEC layer showed an increased viability of the HepG2/C3A cells within the 3D scaffold compared to that of the 3D liver constructs without the HUVEC layer, demonstrating a protective role of the introduced endothelial cell layer. The 3D vascularized liver model presented in this study is anticipated to provide a better and more accurate in vitro liver model system for future drug toxicity testing.

  8. 3D Finite Element Analysis of Particle-Reinforced Aluminum

    NASA Technical Reports Server (NTRS)

    Shen, H.; Lissenden, C. J.

    2002-01-01

    Deformation in particle-reinforced aluminum has been simulated using three distinct types of finite element model: a three-dimensional repeating unit cell, a three-dimensional multi-particle model, and two-dimensional multi-particle models. The repeating unit cell model represents a fictitious periodic cubic array of particles. The 3D multi-particle (3D-MP) model represents randomly placed and oriented particles. The 2D generalized plane strain multi-particle models were obtained from planar sections through the 3D-MP model. These models were used to study the tensile macroscopic stress-strain response and the associated stress and strain distributions in an elastoplastic matrix. The results indicate that the 2D model having a particle area fraction equal to the particle representative volume fraction of the 3D models predicted the same macroscopic stress-strain response as the 3D models. However, there are fluctuations in the particle area fraction in a representative volume element. As expected, predictions from 2D models having different particle area fractions do not agree with predictions from 3D models. More importantly, it was found that the microscopic stress and strain distributions from the 2D models do not agree with those from the 3D-MP model. Specifically, the plastic strain distribution predicted by the 2D model is banded along lines inclined at 45 deg from the loading axis while the 3D model prediction is not. Additionally, the triaxial stress and maximum principal stress distributions predicted by 2D and 3D models do not agree. Thus, it appears necessary to use a multi-particle 3D model to accurately predict material responses that depend on local effects, such as strain-to-failure, fracture toughness, and fatigue life.

  9. Analysis and dynamic 3D visualization of cerebral blood flow combining 3D and 4D MR image sequences

    NASA Astrophysics Data System (ADS)

    Forkert, Nils Daniel; Säring, Dennis; Fiehler, Jens; Illies, Till; Möller, Dietmar; Handels, Heinz

    2009-02-01

    In this paper we present a method for the dynamic visualization of cerebral blood flow. Spatio-temporal 4D magnetic resonance angiography (MRA) image datasets and 3D MRA datasets with high spatial resolution were acquired for the analysis of arteriovenous malformations (AVMs). One of the main tasks is the combination of the information of the 3D and 4D MRA image sequences. Initially, in the 3D MRA dataset the vessel system is segmented and a 3D surface model is generated. Then, temporal intensity curves are analyzed voxelwise in the 4D MRA image sequences. A curve fitting of the temporal intensity curves to a patient individual reference curve is used to extract the bolus arrival times in the 4D MRA sequences. After non-linear registration of both MRA datasets the extracted hemodynamic information is transferred to the surface model where the time points of inflow can be visualized color coded dynamically over time. The dynamic visualizations computed using the curve fitting method for the estimation of the bolus arrival times were rated superior compared to those computed using conventional approaches for bolus arrival time estimation. In summary the procedure suggested allows a dynamic visualization of the individual hemodynamic situation and better understanding during the visual evaluation of cerebral vascular diseases.

  10. 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.

  11. Analysis of ceramic composites by 3D microtomography

    SciTech Connect

    Luethi, T. ); Ellingson, W.A. )

    1991-01-01

    In the first part we describe the use of 3D X-ray microtomography for the analysis of density distributions inside and between cold pressed green state whisker reinforced Si{sub 3}N{sub 4}/Si{sub 3}N{sub 4} bending test specimens. The differences between a changing content of whisker volumes (0 to 35%) show a sharp density reduction between 10 and 15%. This agrees with previous research which shows that maximum density is achieved between 10 and 15% whisker loadings. Since density is directly related to fracture strength, microtomography may be useful as strength prediction. In the second part we describe the use microtomography combined with image processing, especially a 2D FOURIER transform, for the analysis of cloth direction distributions in multidirectional reinforced chemical vapor infiltrated (CVI) SiC/SiC test components. The SiC fibers NICALON{trademark} and were oriented 30, 60, and 90{degrees}. In laying up the cloth, orientations may not be maintained and this impacts the mechanical properties. Use of microtomography with image processing may allow mechanical property variations to be established. 9 refs., 7 figs.

  12. Understanding Crystal Populations; Looking Towards 3D Quantitative Analysis

    NASA Astrophysics Data System (ADS)

    Jerram, D. A.; Morgan, D. J.

    2010-12-01

    In order to understand volcanic systems, the potential record held within crystal populations needs to be revealed. It is becoming increasingly clear, however, that the crystal populations that arrive at the surface in volcanic eruptions are commonly mixtures of crystals, which may be representative of simple crystallization, recycling of crystals and incorporation of alien crystals. If we can quantify the true 3D population within a sample then we will be able to separate crystals with different histories and begin to interrogate the true and complex plumbing within the volcanic system. Modeling crystal populations is one area where we can investigate the best methodologies to use when dealing with sections through 3D populations. By producing known 3D shapes and sizes with virtual textures and looking at the statistics of shape and size when such populations are sectioned, we are able to gain confidence about what our 2D information is telling us about the population. We can also use this approach to test the size of population we need to analyze. 3D imaging through serial sectioning or x-ray CT, provides a complete 3D quantification of a rocks texture. Individual phases can be identified and in principle the true 3D statistics of the population can be interrogated. In practice we need to develop strategies (as with 2D-3D transformations), that enable a true characterization of the 3D data, and an understanding of the errors and pitfalls that exist. Ultimately, the reproduction of true 3D textures and the wealth of information they hold, is now within our reach.

  13. 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.

  14. 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.

  15. 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.

  16. Quantitative analysis of autophagy using advanced 3D fluorescence microscopy.

    PubMed

    Changou, Chun A; Wolfson, Deanna L; Ahluwalia, Balpreet Singh; Bold, Richard J; Kung, Hsing-Jien; Chuang, Frank Y S

    2013-05-03

    Prostate cancer is the leading form of malignancies among men in the U.S. While surgery carries a significant risk of impotence and incontinence, traditional chemotherapeutic approaches have been largely unsuccessful. Hormone therapy is effective at early stage, but often fails with the eventual development of hormone-refractory tumors. We have been interested in developing therapeutics targeting specific metabolic deficiency of tumor cells. We recently showed that prostate tumor cells specifically lack an enzyme (argininosuccinate synthase, or ASS) involved in the synthesis of the amino acid arginine(1). This condition causes the tumor cells to become dependent on exogenous arginine, and they undergo metabolic stress when free arginine is depleted by arginine deiminase (ADI)(1,10). Indeed, we have shown that human prostate cancer cells CWR22Rv1 are effectively killed by ADI with caspase-independent apoptosis and aggressive autophagy (or macroautophagy)(1,2,3). Autophagy is an evolutionarily-conserved process that allows cells to metabolize unwanted proteins by lysosomal breakdown during nutritional starvation(4,5). Although the essential components of this pathway are well-characterized(6,7,8,9), many aspects of the molecular mechanism are still unclear - in particular, what is the role of autophagy in the death-response of prostate cancer cells after ADI treatment? In order to address this question, we required an experimental method to measure the level and extent of autophagic response in cells - and since there are no known molecular markers that can accurately track this process, we chose to develop an imaging-based approach, using quantitative 3D fluorescence microscopy(11,12). Using CWR22Rv1 cells specifically-labeled with fluorescent probes for autophagosomes and lysosomes, we show that 3D image stacks acquired with either widefield deconvolution microscopy (and later, with super-resolution, structured-illumination microscopy) can clearly capture the early

  17. Parameterization of 3D brain structures for statistical shape analysis

    NASA Astrophysics Data System (ADS)

    Zhu, Litao; Jiang, Tianzi

    2004-05-01

    Statistical Shape Analysis (SSA) is a powerful tool for noninvasive studies of pathophysiology and diagnosis of brain diseases. It also provides a shape constraint for the segmentation of brain structures. There are two key problems in SSA: the representation of shapes and their alignments. The widely used parameterized representations are obtained by preserving angles or areas and the alignments of shapes are achieved by rotating parameter net. However, representations preserving angles or areas do not really guarantee the anatomical correspondence of brain structures. In this paper, we incorporate shape-based landmarks into parameterization of banana-like 3D brain structures to address this problem. Firstly, we get the triangulated surface of the object and extract two landmarks from the mesh, i.e. the ends of the banana-like object. Then the surface is parameterized by creating a continuous and bijective mapping from the surface to a spherical surface based on a heat conduction model. The correspondence of shapes is achieved by mapping the two landmarks to the north and south poles of the sphere and using an extracted origin orientation to select the dateline during parameterization. We apply our approach to the parameterization of lateral ventricle and a multi-resolution shape representation is obtained by using the Discrete Fourier Transform.

  18. Crashworthiness analysis using advanced material models in DYNA3D

    SciTech Connect

    Logan, R.W.; Burger, M.J.; McMichael, L.D.; Parkinson, R.D.

    1993-10-22

    As part of an electric vehicle consortium, LLNL and Kaiser Aluminum are conducting experimental and numerical studies on crashworthy aluminum spaceframe designs. They have jointly explored the effect of heat treat on crush behavior and duplicated the experimental behavior with finite-element simulations. The major technical contributions to the state of the art in numerical simulation arise from the development and use of advanced material model descriptions for LLNL`s DYNA3D code. Constitutive model enhancements in both flow and failure have been employed for conventional materials such as low-carbon steels, and also for lighter weight materials such as aluminum and fiber composites being considered for future vehicles. The constitutive model enhancements are developed as extensions from LLNL`s work in anisotropic flow and multiaxial failure modeling. Analysis quality as a function of level of simplification of material behavior and mesh is explored, as well as the penalty in computation cost that must be paid for using more complex models and meshes. The lightweight material modeling technology is being used at the vehicle component level to explore the safety implications of small neighborhood electric vehicles manufactured almost exclusively from these materials.

  19. 3-D Printed Ultem 9085 Testing and Analysis

    NASA Technical Reports Server (NTRS)

    Aguilar, Daniel; Christensen, Sean; Fox, Emmet J.

    2015-01-01

    The purpose of this document is to analyze the mechanical properties of 3-D printed Ultem 9085. This document will focus on the capabilities, limitations, and complexities of 3D printing in general, and explain the methods by which this material is tested. Because 3-D printing is a relatively new process that offers an innovative means to produce hardware, it is important that the aerospace community understands its current advantages and limitations, so that future endeavors involving 3-D printing may be completely safe. This document encompasses three main sections: a Slosh damage assessment, a destructive test of 3-D printed Ultem 9085 samples, and a test to verify simulation for the 3-D printed SDP (SPHERES Docking Port). Described below, 'Slosh' and 'SDP' refer to two experiments that are built using Ultem 9085 for use with the SPHERES (Synchronized Position Hold, Engage, Reorient, Experimental Satellites) program onboard the International Space Station (ISS) [16]. The SPHERES Facility is managed out of the National Aeronautics and Space Administration (NASA) Ames Research Center in California.

  20. 3D image analysis of abdominal aortic aneurysm

    NASA Astrophysics Data System (ADS)

    Subasic, Marko; Loncaric, Sven; Sorantin, Erich

    2001-07-01

    In this paper we propose a technique for 3-D segmentation of abdominal aortic aneurysm (AAA) from computed tomography angiography (CTA) images. Output data (3-D model) form the proposed method can be used for measurement of aortic shape and dimensions. Knowledge of aortic shape and size is very important in planning of minimally invasive procedure that is for selection of appropriate stent graft device for treatment of AAA. The technique is based on a 3-D deformable model and utilizes the level-set algorithm for implementation of the method. The method performs 3-D segmentation of CTA images and extracts a 3-D model of aortic wall. Once the 3-D model of aortic wall is available it is easy to perform all required measurements for appropriate stent graft selection. The method proposed in this paper uses the level-set algorithm for deformable models, instead of the classical snake algorithm. The main advantage of the level set algorithm is that it enables easy segmentation of complex structures, surpassing most of the drawbacks of the classical approach. We have extended the deformable model to incorporate the a priori knowledge about the shape of the AAA. This helps direct the evolution of the deformable model to correctly segment the aorta. The algorithm has been implemented in IDL and C languages. Experiments have been performed using real patient CTA images and have shown good results.

  1. A search for sources of drug resistance by the 4D-QSAR analysis of a set of antimalarial dihydrofolate reductase inhibitors

    NASA Astrophysics Data System (ADS)

    Santos-Filho, Osvaldo Andrade; Hopfinger, Anton J.

    2001-01-01

    A set of 18 structurally diverse antifolates including pyrimethamine, cycloguanil, methotrexate, aminopterin and trimethoprim, and 13 pyrrolo[2,3-d]pyrimidines were studied using four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis. The corresponding biological activities of these compounds include IC50 inhibition constants for both the wild type, and a specific mutant type of Plasmodium falciparum dihydrofolate reductase (DHFR). Two thousand conformations of each analog were sampled to generate a conformational ensemble profile (CEP) from a molecular dynamics simulation (MDS) of 100,000 conformer trajectory states. Each sampled conformation was placed in a 1 Å cubic grid cell lattice for each of five trial alignments. The frequency of occupation of each grid cell was computed for each of six types of pharmacophore groups of atoms of each compound. These grid cell occupancy descriptors (GCODs) were then used as a descriptor pool to construct 4D-QSAR models. Models for inhibition of both the `wild' type and the mutant enzyme were generated which provide detailed spatial pharmacophore requirements for inhibition in terms of atom types and their corresponding relative locations in space. The 4D-QSAR models indicate some structural features perhaps relevant to the mechanism of resistance of the Plasmodium falciparum DHFR to current antimalarials. One feature identified is a slightly different binding alignment of the ligands to the mutant form of the enzyme as compared to the wild type.

  2. Computerized analysis of pelvic incidence from 3D images

    NASA Astrophysics Data System (ADS)

    Vrtovec, Tomaž; Janssen, Michiel M. A.; Pernuš, Franjo; Castelein, René M.; Viergever, Max A.

    2012-02-01

    The sagittal alignment of the pelvis can be evaluated by the angle of pelvic incidence (PI), which is constant for an arbitrary subject position and orientation and can be therefore compared among subjects in standing, sitting or supine position. In this study, PI was measured from three-dimensional (3D) computed tomography (CT) images of normal subjects that were acquired in supine position. A novel computerized method, based on image processing techniques, was developed to automatically determine the anatomical references required to measure PI, i.e. the centers of the femoral heads in 3D, and the center and inclination of the sacral endplate in 3D. Multiplanar image reformation was applied to obtain perfect sagittal views with all anatomical structures completely in line with the hip axis, from which PI was calculated. The resulting PI (mean+/-standard deviation) was equal to 46.6°+/-9.2° for male subjects (N = 189), 47.6°+/-10.7° for female subjects (N = 181), and 47.1°+/-10.0° for all subjects (N = 370). The obtained measurements of PI from 3D images were not biased by acquisition projection or structure orientation, because all anatomical structures were completely in line with the hip axis. The performed measurements in 3D therefore represent PI according to the actual geometrical relationships among anatomical structures of the sacrum, pelvis and hips, as observed from the perfect sagittal views.

  3. 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

  4. 3D image analysis of abdominal aortic aneurysm

    NASA Astrophysics Data System (ADS)

    Subasic, Marko; Loncaric, Sven; Sorantin, Erich

    2002-05-01

    This paper presents a method for 3-D segmentation of abdominal aortic aneurysm from computed tomography angiography images. The proposed method is automatic and requires minimal user assistance. Segmentation is performed in two steps. First inner and then outer aortic border is segmented. Those two steps are different due to different image conditions on two aortic borders. Outputs of these two segmentations give a complete 3-D model of abdominal aorta. Such a 3-D model is used in measurements of aneurysm area. The deformable model is implemented using the level-set algorithm due to its ability to describe complex shapes in natural manner which frequently occur in pathology. In segmentation of outer aortic boundary we introduced some knowledge based preprocessing to enhance and reconstruct low contrast aortic boundary. The method has been implemented in IDL and C languages. Experiments have been performed using real patient CTA images and have shown good results.

  5. Thermal Analysis of 3D Printed 420 Stainless Steel

    NASA Astrophysics Data System (ADS)

    Pawar, Prathamesh Vijay

    Additive manufacturing opens new possibilities in the manufacturing industry. 3D printing is a form of additive manufacturing. 3D printers will have a significant influence over the industrial market, with extremely positive effects in no time. The main aim of this research is to determine the effect of process parameters of Binder Jet manufactured 420 Stainless Steel (420SS) parts on thermal properties such as thermal conductivity. Different parameters, such as layer thickness, sintering time and sintering temperature were varied. A full factorial design of experiment matrix was made by varying these parameters using two levels. Testing showed that different parameters affected the properties in a different manner. Sintering time was very important property as it changed the composition and arrangement of steel and bronze powder during the sintering process. M-flex 3D metal printer by Ex-one was used to print samples of 420SS.

  6. 3D statistical failure analysis of monolithic dental ceramic crowns.

    PubMed

    Nasrin, Sadia; Katsube, Noriko; Seghi, Robert R; Rokhlin, Stanislav I

    2016-07-05

    For adhesively retained ceramic crown of various types, it has been clinically observed that the most catastrophic failures initiate from the cement interface as a result of radial crack formation as opposed to Hertzian contact stresses originating on the occlusal surface. In this work, a 3D failure prognosis model is developed for interface initiated failures of monolithic ceramic crowns. The surface flaw distribution parameters determined by biaxial flexural tests on ceramic plates and point-to-point variations of multi-axial stress state at the intaglio surface are obtained by finite element stress analysis. They are combined on the basis of fracture mechanics based statistical failure probability model to predict failure probability of a monolithic crown subjected to single-cycle indentation load. The proposed method is verified by prior 2D axisymmetric model and experimental data. Under conditions where the crowns are completely bonded to the tooth substrate, both high flexural stress and high interfacial shear stress are shown to occur in the wall region where the crown thickness is relatively thin while high interfacial normal tensile stress distribution is observed at the margin region. Significant impact of reduced cement modulus on these stress states is shown. While the analyses are limited to single-cycle load-to-failure tests, high interfacial normal tensile stress or high interfacial shear stress may contribute to degradation of the cement bond between ceramic and dentin. In addition, the crown failure probability is shown to be controlled by high flexural stress concentrations over a small area, and the proposed method might be of some value to detect initial crown design errors.

  7. Epic Dimensions: a Comparative Analysis of 3d Acquisition Methods

    NASA Astrophysics Data System (ADS)

    Graham, C. A.; Akoglu, K. G.; Lassen, A. W.; Simon, S.

    2017-08-01

    When it comes to capturing the geometry of a cultural heritage artifact, there is certainly no dearth of possible acquisition techniques. As technology has rapidly developed, the availability of intuitive 3D generating tools has increased exponentially and made it possible even for non-specialists to create many models quickly. Though the by-products of these different acquisition methods may be incongruent in terms of quality, these discrepancies are not problematic, as there are many applications of 3D models, each with their own set of requirements. Comparisons of high-resolution 3D models of an iconic Babylonian tablet, captured via four different closerange technologies discussed in this paper assess which methods of 3D digitization best suit specific intended purposes related to research, conservation and education. Taking into consideration repeatability, time and resource implications, qualitative and quantitative potential and ease of use, this paper presents a study of the strengths and weakness of structured light scanning, triangulation laser scanning, photometric stereo and close-range photogrammetry, in the context of interactive investigation, conditions monitoring, engagement, and dissemination.

  8. Analysis of 3D multi-layer microfluidic gradient generator.

    PubMed

    Ha, Jang Ho; Kim, Tae Hyeon; Lee, Jong Min; Ahrberg, Christian D; Chung, Bong Geun

    2017-01-01

    We developed a three-dimensional (3D) simple multi-layer microfluidic gradient generator to create molecular gradients on the centimeter scale with a wide range of flow rates. To create the concentration gradients, a main channel (MC) was orthogonally intersected with vertical side microchannel (SC) in a 3D multi-layer microfluidic device. Through sequential dilution from the SC, a spatial gradient was generated in the MC. Two theoretical models were created to assist in the design of the 3D multi-layer microfluidic gradient generator and to compare its performance against a two-dimensional equivalent. A first mass balance model was used to predict the steady-state concentrations reached, while a second computational fluid dynamic model was employed to predict spatial development of the gradient by considering convective as well as diffusive mass transport. Furthermore, the theoretical simulations were verified through experiments to create molecular gradients in a 3D multi-layer microfluidic gradient generator. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Efficiency analysis for 3D filtering of multichannel images

    NASA Astrophysics Data System (ADS)

    Kozhemiakin, Ruslan A.; Rubel, Oleksii; Abramov, Sergey K.; Lukin, Vladimir V.; Vozel, Benoit; Chehdi, Kacem

    2016-10-01

    Modern remote sensing systems basically acquire images that are multichannel (dual- or multi-polarization, multi- and hyperspectral) where noise, usually with different characteristics, is present in all components. If noise is intensive, it is desirable to remove (suppress) it before applying methods of image classification, interpreting, and information extraction. This can be done using one of two approaches - by component-wise or by vectorial (3D) filtering. The second approach has shown itself to have higher efficiency if there is essential correlation between multichannel image components as this often happens for multichannel remote sensing data of different origin. Within the class of 3D filtering techniques, there are many possibilities and variations. In this paper, we consider filtering based on discrete cosine transform (DCT) and pay attention to two aspects of processing. First, we study in detail what changes in DCT coefficient statistics take place for 3D denoising compared to component-wise processing. Second, we analyze how selection of component images united into 3D data array influences efficiency of filtering and can the observed tendencies be exploited in processing of images with rather large number of channels.

  10. QSAR analysis for ADA upon interaction with a series of adenine derivatives as inhibitors.

    PubMed

    Moosavi-Movahedi, A A; Safarian, S; Hakimelahi, G H; Ataei, G; Ajloo, D; Panjehpour, S; Riahi, S; Mousavi, M F; Mardanyan, S; Soltani, N; Khalafi-Nezhad, A; Sharghi, H; Moghadamnia, H; Saboury, A A

    2004-01-01

    The kinetic parameters of adenosine deaminase such as Km and Ki were determined in the absence and presence of adenine derivatives (R1-R24) in sodium phosphate buffer (50 mM; pH 7.5) solution at 27 degrees C. These kinetic parameters were used for QSAR analysis. As such, we found some theoretical descriptors to which the binding affinity of adenosine deaminase (ADA) towards several adenine nucleosides as inhibitors is correlated. QSAR analysis has revealed that binding affinity of the adenine nucleosides upon interaction with ADA depends on the molecular volume, dipole moment of the molecule, electric charge around the N1 atom, and the highest of positive charge for the related molecules.

  11. Reliability of 3D upper limb motion analysis in children with obstetric brachial plexus palsy.

    PubMed

    Mahon, Judy; Malone, Ailish; Kiernan, Damien; Meldrum, Dara

    2017-03-01

    Kinematics, measured by 3D upper limb motion analysis (3D-ULMA), can potentially increase understanding of movement patterns by quantifying individual joint contributions. Reliability in children with obstetric brachial plexus palsy (OBPP) has not been established.

  12. Metrology and Failure Analysis for 3D IC Integration

    SciTech Connect

    Zschech, Ehrenfried; Diebold, Alain

    2011-11-10

    At the same time as research in 3D TSV technology is advancing quickly, the analytical techniques used in the evaluation of 3D stacks must also advance in capability. Microscopy techniques for which silicon is opaque such as scanning acoustic microscopy (SAM) and confocal infrared (IR) microscopy are capable of inspecting the interface between bonded wafer pairs, while high resolution X-ray computed tomography (XCT) is used to detect voids in TSVs. With nano-XCT, voids in copper TSVs with sub-100 nm size can be visualized. For more detailed failure characterization, a target Focused Ion Beam (FIB) cross-section through the localized region of interest (defect) and subsequent scanning electron microscopy (SEM) imaging is proposed. Currently, the most important requirement is to reduce the so-called time-to-data, e. g. for defect localization using nano-XCT and for cross-section characterization.

  13. Experimental 3-D SAR Human Target Signature Analysis

    DTIC Science & Technology

    2014-07-21

    through the wall structure that the radar signal must travel to get to the target, such as through and around studs . The different features from the...drywall made of wood stud , gypsum, insulating material, and vinyl coating. The second wall structure is made of cinder blocks and is a more challenging... wall synthetic aperture radar (SAR) imaging from an experimental L-band through- wall SAR prototype. Tools and algorithms for 3-D visualization are

  14. Analysis of 3-D Propagation Effects Due to Environmental Variability

    DTIC Science & Technology

    2014-09-30

    presence of 3-D environmental variations, especially shelf break canyons . Work was also performed in support of 2-D propagation in shallow water to...propagation in the Monterey Bay Canyon . This was motivated by observations of highly variable directional features in measured acoustic vector data...Rev. 8-98) Prescribed by ANSI Std Z39-18 2 the Monterey Bay Canyon were used as inputs to the model, and broadband calculations were performed

  15. 3D Display Calibration by Visual Pattern Analysis.

    PubMed

    Hwang, Hyoseok; Chang, Hyun Sung; Nam, Dongkyung; Kweon, In So

    2017-02-06

    Nearly all 3D displays need calibration for correct rendering. More often than not, the optical elements in a 3D display are misaligned from the designed parameter setting. As a result, 3D magic does not perform well as intended. The observed images tend to get distorted. In this paper, we propose a novel display calibration method to fix the situation. In our method, a pattern image is displayed on the panel and a camera takes its pictures twice at different positions. Then, based on a quantitative model, we extract all display parameters (i.e., pitch, slanted angle, gap or thickness, offset) from the observed patterns in the captured images. For high accuracy and robustness, our method analyzes the patterns mostly in frequency domain. We conduct two types of experiments for validation; one with optical simulation for quantitative results and the other with real-life displays for qualitative assessment. Experimental results demonstrate that our method is quite accurate, about a half order of magnitude higher than prior work; is efficient, spending less than 2 s for computation; and is robust to noise, working well in the SNR regime as low as 6 dB.

  16. 3D analysis of deformation bands in unconsolidated Pleistocene sediments

    NASA Astrophysics Data System (ADS)

    Tanner, David C.; Brandes, Christian

    2010-05-01

    Deformation bands are planar structural elements that occur in porous sandstones, even in the unconsolidated state (e.g. Aydin, 1978, Fossen et al., 2007). Whereas faults are discrete surfaces, deformation bands are much thicker, tabular zones of continuous displacement (Draganits et al. 2005). They have attracted much attention in the past because of their low permeabilities and their potential impact on fluid flow in sedimentary basins (e.g. Fossen & Bale, 2007). We present an outcrop-based study on the 3D geometry and strain of deformation band faults, which developed in Pleistocene unconsolidated sands in northern Germany. We digitally photographed a 150 × 150 cm square, near-vertical outcrop wall in a quarry, against an orthogonal scale. Then 15 cm of sand was scraped away and the procedure repeated. A total of ten sections were procured. The photographs were interpreted for upper and lower boundaries of the deformation band faults and distinctive stratigraphic horizons. The sections were then imported into Move2009.1 (Midland Valley Exploration Ltd, 2009) with the correct orientation and scale. Using the Move2009.1 software, we analysed the thickness of the deformation band faults, along-strike displacement of beds along the faults, and the total extension caused by faulting. The three-dimensional model is cut by a set of nine major deformation band faults, all with a normal sense of displacement; one set of six faults strike SE-NW, dipping NE by ca. 50o, the other set of three faults strike NNE-SSW, dipping WSW by ca. 45o. The former cross-cut the latter, thus their age relationship is shown. In the dip direction the faults are straight, but slightly arcuate in their strike direction. We identified seven distinct stratigraphic horizons, from which we were able to analyse along-strike displacement and total extension due to faulting. The three dimensional model shows that thickness of the deformation band faults varies elliptically and ranges from zero to 4

  17. Seeing More Is Knowing More: V3D Enables Real-Time 3D Visualization and Quantitative Analysis of Large-Scale Biological Image Data Sets

    NASA Astrophysics Data System (ADS)

    Peng, Hanchuan; Long, Fuhui

    Everyone understands seeing more is knowing more. However, for large-scale 3D microscopic image analysis, it has not been an easy task to efficiently visualize, manipulate and understand high-dimensional data in 3D, 4D or 5D spaces. We developed a new 3D+ image visualization and analysis platform, V3D, to meet this need. The V3D system provides 3D visualization of gigabyte-sized microscopy image stacks in real time on current laptops and desktops. V3D streamlines the online analysis, measurement and proofreading of complicated image patterns by combining ergonomic functions for selecting a location in an image directly in 3D space and for displaying biological measurements, such as from fluorescent probes, using the overlaid surface objects. V3D runs on all major computer platforms and can be enhanced by software plug-ins to address specific biological problems. To demonstrate this extensibility, we built a V3Dbased application, V3D-Neuron, to reconstruct complex 3D neuronal structures from high-resolution brain images. V3D-Neuron can precisely digitize the morphology of a single neuron in a fruitfly brain in minutes, with about a 17-fold improvement in reliability and tenfold savings in time compared with other neuron reconstruction tools. Using V3D-Neuron, we demonstrate the feasibility of building a high-resolution 3D digital atlas of neurite tracts in the fruitfly brain. V3D can be easily extended using a simple-to-use and comprehensive plugin interface.

  18. Discovery of DPP IV inhibitors by pharmacophore modeling and QSAR analysis followed by in silico screening.

    PubMed

    Al-Masri, Ihab M; Mohammad, Mohammad K; Taha, Mutasem O

    2008-11-01

    Dipeptidyl peptidase IV (DPP IV) deactivates the natural hypoglycemic incretin hormones. Inhibition of this enzyme should restore glucose homeostasis in diabetic patients making it an attractive target for the development of new antidiabetic drugs. With this in mind, the pharmacophoric space of DPP IV was explored using a set of 358 known inhibitors. Thereafter, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and physicochemical descriptors that yield selfconsistent and predictive quantitative structure-activity relationships (QSAR) (r(2) (287)=0.74, F-statistic=44.5, r(2) (BS)=0.74, r(2) (LOO)=0.69, r(2) (PRESS) against 71 external testing inhibitors=0.51). Two orthogonal pharmacophores (of cross-correlation r(2)=0.23) emerged in the QSAR equation suggesting the existence of at least two distinct binding modes accessible to ligands within the DPP IV binding pocket. Docking experiments supported the binding modes suggested by QSAR/pharmacophore analyses. The validity of the QSAR equation and the associated pharmacophore models were established by the identification of new low-micromolar anti-DPP IV leads retrieved by in silico screening. One of our interesting potent anti-DPP IV hits is the fluoroquinolone gemifloxacin (IC(50)=1.12 muM). The fact that gemifloxacin was recently reported to potently inhibit the prodiabetic target glycogen synthase kinase 3beta (GSK-3beta) suggests that gemifloxacin is an excellent lead for the development of novel dual antidiabetic inhibitors against DPP IV and GSK-3beta.

  19. 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.

  20. Customisable 3D printed microfluidics for integrated analysis and optimisation.

    PubMed

    Monaghan, T; Harding, M J; Harris, R A; Friel, R J; Christie, S D R

    2016-08-16

    The formation of smart Lab-on-a-Chip (LOC) devices featuring integrated sensing optics is currently hindered by convoluted and expensive manufacturing procedures. In this work, a series of 3D-printed LOC devices were designed and manufactured via stereolithography (SL) in a matter of hours. The spectroscopic performance of a variety of optical fibre combinations were tested, and the optimum path length for performing Ultraviolet-visible (UV-vis) spectroscopy determined. The information gained in these trials was then used in a reaction optimisation for the formation of carvone semicarbazone. The production of high resolution surface channels (100-500 μm) means that these devices were capable of handling a wide range of concentrations (9 μM-38 mM), and are ideally suited to both analyte detection and process optimisation. This ability to tailor the chip design and its integrated features as a direct result of the reaction being assessed, at such a low time and cost penalty greatly increases the user's ability to optimise both their device and reaction. As a result of the information gained in this investigation, we are able to report the first instance of a 3D-printed LOC device with fully integrated, in-line monitoring capabilities via the use of embedded optical fibres capable of performing UV-vis spectroscopy directly inside micro channels.

  1. Wear Analysis of Thermal Spray Coatings on 3D Surfaces

    NASA Astrophysics Data System (ADS)

    Tillmann, W.; Luo, W.; Selvadurai, U.

    2014-01-01

    Even though the application of thermal spray coatings on complex geometries gained a greater interest in the last decade, the effect of different geometrical features on the wear behavior is still ill-defined. In this study, the wear resistance of FTC-FeCSiMn coated 3D surfaces was investigated. The wear test was carried out by means of two innovative testing procedures. The first test is a Pin-on-Tubes test where the rotating motion is realized by a lathe chuck. The specimens in the second test were fixed on the table and a robot arm operated the pin. This wear test was applied on specimens with concave or convex surfaces. The residual stresses, which were determined by means of an incremental hole-drilling method, show a dependency on the substrate geometry. The obtained stresses were put in relation to the different radii. After the wear test, a 3D-profilometer determined the wear volume and the sections of the coatings were characterized by a scanning electron microscope. The results indicate that the wear resistance is strongly influenced by the geometry of the substrate.

  2. 3D motion analysis of keratin filaments in living cells

    NASA Astrophysics Data System (ADS)

    Herberich, Gerlind; Windoffer, Reinhard; Leube, Rudolf; Aach, Til

    2010-03-01

    We present a novel and efficient approach for 3D motion estimation of keratin intermediate filaments in vitro. Keratin filaments are elastic cables forming a complex scaffolding within epithelial cells. To understand the mechanisms of filament formation and network organisation under physiological and pathological conditions, quantitative measurements of dynamic network alterations are essential. Therefore we acquired time-lapse series of 3D images using a confocal laser scanning microscope. Based on these image series, we show that a dense vector field can be computed such that the displacements from one frame to the next can be determined. Our method is based on a two-step registration process: First, a rigid pre-registration is applied in order to compensate for possible global cell movement. This step enables the subsequent nonrigid registration to capture only the sought local deformations of the filaments. As the transformation model of the deformable registration algorithm is based on Free Form Deformations, it is well suited for modeling filament network dynamics. The optimization is performed using efficient linear programming techniques such that the huge amount of image data of a time series can be efficiently processed. The evaluation of our results illustrates the potential of our approach.

  3. Metrological analysis of the human foot: 3D multisensor exploration

    NASA Astrophysics Data System (ADS)

    Muñoz Potosi, A.; Meneses Fonseca, J.; León Téllez, J.

    2011-08-01

    In the podiatry field, many of the foot dysfunctions are mainly generated due to: Congenital malformations, accidents or misuse of footwear. For the treatment or prevention of foot disorders, the podiatrist diagnoses prosthesis or specific adapted footwear, according to the real dimension of foot. Therefore, it is necessary to acquire 3D information of foot with 360 degrees of observation. As alternative solution, it was developed and implemented an optical system of threedimensional reconstruction based in the principle of laser triangulation. The system is constituted by an illumination unit that project a laser plane into the foot surface, an acquisition unit with 4 CCD cameras placed around of axial foot axis, an axial moving unit that displaces the illumination and acquisition units in the axial axis direction and a processing and exploration unit. The exploration software allows the extraction of distances on three-dimensional image, taking into account the topography of foot. The optical system was tested and their metrological performances were evaluated in experimental conditions. The optical system was developed to acquire 3D information in order to design and make more appropriate footwear.

  4. Spontaneous Facial Motility in Infancy: A 3D Kinematic Analysis

    PubMed Central

    Green, Jordan R.; Wilson, Erin M.

    2008-01-01

    Early spontaneous orofacial movements have rarely been studied experimentally, though the motor experiences gained from these behaviors may influence the development of motor skills emerging for speech. This investigation quantitatively describes developmental changes in silent, spontaneous lip and jaw movements from 1 to 12 months of age using optically based 3D motion capture technology. Twenty-nine typically developing infants at five ages (1, 5, 7, 9, and 12 months) were studied cross-sectionally. Infants exhibited spontaneous facial movements at all ages studied. Several age-related changes were detected in lip and jaw kinematics: the occurrence of spontaneous movements increased, movement speed increased, the duration of movement epochs decreased and movement coupling among different facial regions increased. Additionally, evidence for stereotypic movements was not strong. The present findings suggest that, during the first year of life, early spontaneous facial movements undergo significant developmental change in the direction of skill development for speech. PMID:16381029

  5. Analysis of patient movement during 3D USCT data acquisition

    NASA Astrophysics Data System (ADS)

    Ruiter, N. V.; Hopp, T.; Zapf, M.; Kretzek, E.; Gemmeke, H.

    2016-04-01

    In our first clinical study with a full 3D Ultrasound Computer Tomography (USCT) system patient data was acquired in eight minutes for one breast. In this paper the patient movement during the acquisition was analyzed quantitatively and as far as possible corrected in the resulting images. The movement was tracked in ten successive reflectivity reconstructions of full breast volumes acquired during 10 s intervals at different aperture positions, which were separated by 41 s intervals. The mean distance between initial and final position was 2.2 mm (standard deviation (STD) +/- 0.9 mm, max. 4.1 mm, min. 0.8 mm) and the average sum of all moved distances was 4.9 mm (STD +/- 1.9 mm, max. 8.8 mm, min. 2.7 mm). The tracked movement was corrected by summing successive images, which were transformed according to the detected movement. The contrast of these images increased and additional image content became visible.

  6. Analysis on 3d Topography Effects on Magnetotelluric Responses

    NASA Astrophysics Data System (ADS)

    Nam, M.; Han, N.; Kim, H.; Song, Y.

    2010-12-01

    Magnetotelluric (MT) surveys based on a natural electromagnetic induction in the Earth have been conducted to investigate geothermal resources in Pohang, Jeju Island, and Seokmo Island, Korea. Although some of the MT surveys indicated fracture systems through which relatively high-temperature fluid flows, the temperature is still not enough for a traditional geothermal power plant. However, even when natural convective hydrothermal resources are unavailable, an enhanced geothermal system (EGS), a new type of geothermal power technologies, can produce heat and electricity by harnessing the energy from hot rock at depths ranging from about 3 km to 10 km. This fact makes EGS a hot issue in Korea for geothermal power plant, even though EGS not only has lower capacity of power generation than the traditional one but also more expensive. As a starting stage of site characterization for EGS, which will be followed by temperature and stress estimation, precise interpretation of MT data distorted by irregular surface terrain is critical in Korea, since almost 70% of the land of Korea is mountainous terrain. This study investigates topography effects on MT responses, i.e., apparent resistivities, phases, tippers and induction vectors for a three-dimensional (3D) hill model. To calculate MT responses for a model with surface topography, we use a 3D MT modeling algorithm based on an edge finite-element method. Numerical experiments indicate that current distortion by surface topography affects MT responses such as apparent resistivites, phases, and tippers. Apparent resistivities in the xy mode are slightly higher than the background resistivity near hill slopes in the x-direction while the resistivities are smaller over the hill. Distortions on amplitudes of tippers over a hill are quite similar to those over a valley. The directions of tippers over a hill are toward the summit of the hill, while those over a valley are toward the base.

  7. DYNA3D analysis of the DT-20 shipping container

    SciTech Connect

    Logan, R.W.; Lovejoy, S.C.

    1991-08-22

    A DYNA3D model of the DT-20 shipping container was constructed. Impact onto a rigid steel surface at a velocity of 44 ft/sec (30 foot gravity drop) was studied. The orientation of most interest was a side-drop, but end and corner drops were also studied briefly. The assembly for the baseline side impact contained a 150 lb. payload. During this drop, the outer drum sustains plastic strains of up to 0.15, with most the deformation near the rim. The plywood/Celotex packing is crushed about 3 inches. The inner sealed can sees significant stresses, but barely reaches the onset of yielding in some local areas. Based on hand calculations, the bolts joining the can halves could see stresses near 50 ksi. It is felt that overall, the container should survive this drop. However, detailed modeling of the rim closure and the center bolted joint was not possible due to time constraints. Furthermore, better material models and properties are needed for the Celotex, plywood, and honeycomb in particular. 39 figs., 1 tab.

  8. When Plans Change: Task Analysis and Taxonomy of 3-D Situation Awareness Challenges of UAV Replanning

    DTIC Science & Technology

    2010-06-01

    3-D difficulties, we conducted a cognitive task analysis of the replanning problem with the Navy?s VC-6 Squadron recently returned from Iraq . Key 3-D...the Navy’s VC-6 Squadron recently returned from Iraq . Key 3-D spatial challenges involved rationalizing complex combinations of avoiding airspace and...conducted a requirements analysis of the replanning problem with Navy UAV operators recently returned from the war in Iraq , and report our findings

  9. A study of the relationship between cornea permeability and eye irritation using membrane-interaction QSAR analysis.

    PubMed

    Li, Yi; Liu, Jianzhong; Pan, Dahua; Hopfinger, A J

    2005-12-01

    A methodology termed membrane-interaction QSAR (MI-QSAR) analysis has been used to develop QSAR models to predict drug permeability coefficients across cornea and its component layers (epithelium, stroma, and endothelium). From a training set of 25 structurally diverse drugs, significant QSAR models are constructed and compared for the permeability of the cornea, epithelium, and stroma plus endothelium. Cornea permeability is found to depend on the measured distribution coefficient of the drug, the cohesive energy of the drug, the total potential energy of the drug-membrane "complex," and three other energy refinement descriptor terms. The endothelium may be a more important barrier in cornea permeation than the stroma. Moreover, an investigation of the correlation between cornea permeation and eye irritation is presented as an example of a cross study on different ADMET properties using MI-QSAR analysis. Thirteen structurally diverse drugs, whose molar-adjusted eye irritation scores (MES) have been measured using the Draize rabbit-eye test, were chosen as an eye irritation comparison set. A poor correlation (R(2) = 0.0232) between the MES measures and the predicted cornea permeability coefficients for the drugs in the eye irritation set suggests there is no significant relationship between eye irritation potency and the cornea permeability.

  10. The importance of molecular structures, endpoints' values, and predictivity parameters in QSAR research: QSAR analysis of a series of estrogen receptor binders.

    PubMed

    Li, Jiazhong; Gramatica, Paola

    2010-11-01

    Quantitative structure-activity relationship (QSAR) methodology aims to explore the relationship between molecular structures and experimental endpoints, producing a model for the prediction of new data; the predictive performance of the model must be checked by external validation. Clearly, the qualities of chemical structure information and experimental endpoints, as well as the statistical parameters used to verify the external predictivity have a strong influence on QSAR model reliability. Here, we emphasize the importance of these three aspects by analyzing our models on estrogen receptor binders (Endocrine disruptor knowledge base (EDKB) database). Endocrine disrupting chemicals, which mimic or antagonize the endogenous hormones such as estrogens, are a hot topic in environmental and toxicological sciences. QSAR shows great values in predicting the estrogenic activity and exploring the interactions between the estrogen receptor and ligands. We have verified our previously published model for additional external validation on new EDKB chemicals. Having found some errors in the used 3D molecular conformations, we redevelop a new model using the same data set with corrected structures, the same method (ordinary least-square regression, OLS) and DRAGON descriptors. The new model, based on some different descriptors, is more predictive on external prediction sets. Three different formulas to calculate correlation coefficient for the external prediction set (Q2 EXT) were compared, and the results indicated that the new proposal of Consonni et al. had more reasonable results, consistent with the conclusions from regression line, Williams plot and root mean square error (RMSE) values. Finally, the importance of reliable endpoints values has been highlighted by comparing the classification assignments of EDKB with those of another estrogen receptor binders database (METI): we found that 16.1% assignments of the common compounds were opposite (20 among 124 common

  11. 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.

  12. Computational identification of novel histone deacetylase inhibitors by docking based QSAR.

    PubMed

    Nair, Syam B; Teli, Mahesh Kumar; Pradeep, H; Rajanikant, G K

    2012-06-01

    Histone deacetylases (HDACs) are enzymes that modify chromatin structure and contribute to aberrant gene expression in cancer. A series compounds with well-assigned HDAC inhibitory activity was used for docking based 3D-QSAR analysis. The 3D-QSAR acquired had excellent correlation coefficient value (q2=0.753) and high Fisher ratio (F=300.2). A validated pharmacophore model (AAAPR) was employed for virtual screening. After manual selection, molecular docking and further refinement, six compounds with good absorption, distribution, metabolism, and excretion (ADME) properties were selected as potential HDAC inhibitors. Further, the molecular interactions of these inhibitors with the HDAC active site residues were discussed in detail.

  13. RETRAN-3D MOD003 Peach Bottom Turbine Trip 2 Multidimensional Kinetics Analysis Models and Results

    SciTech Connect

    Mori, Michitsugu; Ogura, Katsunori; Gose, Garry C.; Wu, J.-Y

    2003-04-15

    An analysis of the Peach Bottom Unit 2 Turbine Trip Test 2 (PB2/TT2) has been performed using RETRAN-3D MOD003. The purpose of the analysis was to investigate the PB2/TT2 overpressurization transient using the RETRAN-3D multidimensional kinetics model.

  14. Design, Synthesis, Antifungal Activities and 3D-QSAR of New N,N′-Diacylhydrazines Containing 2,4-Dichlorophenoxy Moiety

    PubMed Central

    Sun, Na-Bo; Shi, Yan-Xia; Liu, Xing-Hai; Ma, Yi; Tan, Cheng-Xia; Weng, Jian-Quan; Jin, Jian-Zhong; Li, Bao-Ju

    2013-01-01

    A series of new N,N′-diacylhydrazine derivatives were designed and synthesized. Their structures were verified by 1H-NMR, mass spectra (MS) and elemental analysis. The antifungal activities of these N,N′-diacylhydrazines were evaluated. The bioassay results showed that most of these N,N′-diacylhydrazines showed excellent antifungal activities against Cladosporium cucumerinum, Corynespora cassiicola, Sclerotinia sclerotiorum, Erysiphe cichoracearum, and Colletotrichum orbiculare in vivo. The half maximal effective concentration (EC50) of one of the compounds was also determined, and found to be comparable with a commercial drug. To further investigate the structure–activity relationship, comparative molecular field analysis (CoMFA) was performed on the basis of antifungal activity data. Both the steric and electronic field distributions of CoMFA are in good agreement in this study. PMID:24189221

  15. Molecular modeling study for the design of novel acetyl-CoA carboxylase inhibitors using 3D QSAR, molecular docking and dynamic simulations.

    PubMed

    Vyas, Vivek K; Dabasia, Mohini; Qureshi, Gulamnizami; Patel, Palak; Ghate, Manjunath

    2017-07-01

    Acetyl-CoA carboxylase (ACC) enzyme plays an important role in the regulation of biosynthesis and oxidation of fatty acids. ACC is a recognized drug target for the treatment of obesity and diabetes. Combination of ligand and structure-based in silico methods along with activity and toxicity prediction provides best lead compounds in the drug discovery process. In this study, a data-set of 100 ACC inhibitors were used for the development of comparative molecular field analysis (CoMFA) and comparative molecular similarity index matrix analysis (CoMSIA) models. The generated contour maps were used for the design of novel ACC inhibitors. CoMFA and CoMSIA models were used for the predication of activity of designed compounds. In silico toxicity risk prediction study was carried out for the designed compounds. Molecular docking and dynamic simulations studies were performed to know the binding mode of designed compounds with the ACC enzyme. The designed compounds showed interactions with key amino acid residues important for catalysis, and good correlation was observed between binding free energy and inhibition of ACC.

  16. Design, synthesis, biological activities, and 3D-QSAR of new N,N'-diacylhydrazines containing 2-(2,4-dichlorophenoxy)propane moiety.

    PubMed

    Liu, Xing-Hai; Pan, Li; Ma, Yi; Weng, Jian-Quan; Tan, Cheng-Xia; Li, Yong-Hong; Shi, Yan-Xia; Li, Bao-Ju; Li, Zheng-Ming; Zhang, Yong-Gang

    2011-10-01

    A series of new N,N'-diacylhydrazine derivatives were synthesized efficiently under microwave irradiation. Their structures were characterized by (1) H NMR, MS, and elemental analysis. Various biological activities of these compounds were tested. Most of them exhibited higher herbicidal activities against dicotyledonous weeds than monocotyledonous weeds. In addition, favorable in vivo fungicidal activities were also found of these compounds against Cladosporium cucumerinum, Corynespora cassiicola, Sclerotinia sclerotiorum(Lib.)de Bary, Erysiphe cichoracearum, and Colletotrichum orbiculare (Berk aLMont) Arx. All compounds displayed excellent plant growth regulatory activities: 100% inhibition was achieved against the radicle growth of cucumber. To further investigate the structure-activity relationship, comparative molecular field analysis was performed on the basis of herbicidal activity data, resulting in a statistically reliable model with good predictive power (r(2) = 0.913, q(2) =0.556). Based on the calculation, five additional novel compounds were designed and synthesized. Satisfyingly, compound 4u displayed excellent herbicidal activity (94.7%) at 1500 g/ha, although it is less active than 2,4-D. Meanwhile, this compound also exhibited good fungicidal activity against C. orbiculare (Berk aLMont) Arx (82.16%). © 2011 John Wiley & Sons A/S.

  17. 3D-QSAR and Molecular Docking Studies on the TcPMCA1-Mediated Detoxification of Scopoletin and Coumarin Derivatives.

    PubMed

    Hou, Qiu-Li; Luo, Jin-Xiang; Zhang, Bing-Chuan; Jiang, Gao-Fei; Ding, Wei; Zhang, Yong-Qiang

    2017-06-27

    The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is an economically important agricultural pest that is difficult to prevent and control. Scopoletin is a botanical coumarin derivative that targets Ca(2+)-ATPase to exert a strong acaricidal effect on carmine spider mites. In this study, the full-length cDNA sequence of a plasma membrane Ca(2+)-ATPase 1 gene (TcPMCA1) was cloned. The sequence contains an open reading frame of 3750 bp and encodes a putative protein of 1249 amino acids. The effects of scopoletin on TcPMCA1 expression were investigated. TcPMCA1 was significantly upregulated after it was exposed to 10%, 30%, and 50% of the lethal concentration of scopoletin. Homology modeling, molecular docking, and three-dimensional quantitative structure-activity relationships were then studied to explore the relationship between scopoletin structure and TcPMCA1-inhibiting activity of scopoletin and other 30 coumarin derivatives. Results showed that scopoletin inserts into the binding cavity and interacts with amino acid residues at the binding site of the TcPMCA1 protein through the driving forces of hydrogen bonds. Furthermore, CoMFA (comparative molecular field analysis)- and CoMSIA (comparative molecular similarity index analysis)-derived models showed that the steric and H-bond fields of these compounds exert important influences on the activities of the coumarin compounds.Notably, the C3, C6, and C7 positions in the skeletal structure of the coumarins are the most suitable active sites. This work provides insights into the mechanism underlying the interaction of scopoletin with TcPMCA1. The present results can improve the understanding on plasma membrane Ca(2+)-ATPase-mediated (PMCA-mediated) detoxification of scopoletin and coumarin derivatives in T. cinnabarinus, as well as provide valuable information for the design of novel PMCA-inhibiting acaricides.

  18. 3D-QSAR and Molecular Docking Studies on the TcPMCA1-Mediated Detoxification of Scopoletin and Coumarin Derivatives

    PubMed Central

    Luo, Jin-Xiang; Zhang, Bing-Chuan; Jiang, Gao-Fei; Ding, Wei; Zhang, Yong-Qiang

    2017-01-01

    The carmine spider mite, Tetranychus cinnabarinus (Boisduval), is an economically important agricultural pest that is difficult to prevent and control. Scopoletin is a botanical coumarin derivative that targets Ca2+-ATPase to exert a strong acaricidal effect on carmine spider mites. In this study, the full-length cDNA sequence of a plasma membrane Ca2+-ATPase 1 gene (TcPMCA1) was cloned. The sequence contains an open reading frame of 3750 bp and encodes a putative protein of 1249 amino acids. The effects of scopoletin on TcPMCA1 expression were investigated. TcPMCA1 was significantly upregulated after it was exposed to 10%, 30%, and 50% of the lethal concentration of scopoletin. Homology modeling, molecular docking, and three-dimensional quantitative structure-activity relationships were then studied to explore the relationship between scopoletin structure and TcPMCA1-inhibiting activity of scopoletin and other 30 coumarin derivatives. Results showed that scopoletin inserts into the binding cavity and interacts with amino acid residues at the binding site of the TcPMCA1 protein through the driving forces of hydrogen bonds. Furthermore, CoMFA (comparative molecular field analysis)- and CoMSIA (comparative molecular similarity index analysis)-derived models showed that the steric and H-bond fields of these compounds exert important influences on the activities of the coumarin compounds.Notably, the C3, C6, and C7 positions in the skeletal structure of the coumarins are the most suitable active sites. This work provides insights into the mechanism underlying the interaction of scopoletin with TcPMCA1. The present results can improve the understanding on plasma membrane Ca2+-ATPase-mediated (PMCA-mediated) detoxification of scopoletin and coumarin derivatives in T. cinnabarinus, as well as provide valuable information for the design of novel PMCA-inhibiting acaricides. PMID:28653986

  19. Synthesis, crystal structure, herbicidal activities and 3D-QSAR study of some novel 1,2,4-triazolo[4,3-a]pyridine derivatives.

    PubMed

    Liu, Xing-Hai; Xu, Xiao-Yan; Tan, Cheng-Xia; Weng, Jian-Quan; Xin, Jia-Hua; Chen, Jie

    2015-02-01

    1,2,4-Triazolo[4,3-a]pyridine derivatives represent a new series of compounds that possess good herbicidal activity against Echinochloa crusgalli (L.) Beauv., Setaria faberii, Digitaria sanguinalis (L.) Scop., Brassica juncea Coss., Amaranthus retroflexus L. and Eclipta prostrata L. A total of 23 novel 1,2,4-triazolo[4,3-a]pyridine derivatives were synthesised and identified by (1) H NMR, IR, single-crystal X-ray diffraction, mass-spectroscopic and elemental analysis, and their herbicidal activities were tested against E. crusgalli (L.) Beauv., S. faberii, D. sanguinalis (L.) Scop., B. juncea Coss., A. retroflexus L. and E. prostrata L. at 150 g a.i. ha(-1) . It was found that the title compound 8-chloro-3-(4-propylphenyl)-[1,2,4]-triazolo[4,3-a]pyridine possesses high herbicidal activity and a broad spectrum against the 22 test weeds, with an inhibition effect of about 50% at a dosage of 37.5 g a.i. ha(-1) , and is safe for corn, cotton and rice at a dosage of 150 g a.i. ha(-1) . Furthermore, comparative molecular field analysis contour models were established to study the structure-activity relationship of the title compounds. It is possible that, with further structure modification, 1,2,4-triazolo[4,3-a]pyridine derivatives, which possess good herbicidal activities, may become novel lead compounds for the development of herbicides against dicotyledonous weeds. © 2014 Society of Chemical Industry.

  20. Vibration Analysis using 3D Image Correlation Technique

    NASA Astrophysics Data System (ADS)

    Siebert, T.; Splitthof, K.

    2010-06-01

    Digital speckle correlation techniques have already been successfully proven to be an accurate displacement analysis tool for a wide range of applications. With the use of two cameras, three dimensional measurements of contours and displacements can be carried out. With a simple setup it opens a wide range of applications. Rapid new developments in the field of digital imaging and computer technology opens further applications for these measurement methods to high speed deformation and strain analysis, e.g. in the fields of material testing, fracture mechanics, advanced materials and component testing. The high resolution of the deformation measurements in space and time opens a wide range of applications for vibration analysis of objects. Since the system determines the absolute position and displacements of the object in space, it is capable of measuring high amplitudes and even objects with rigid body movements. The absolute resolution depends on the field of view and is scalable. Calibration of the optical setup is a crucial point which will be discussed in detail. Examples of the analysis of harmonic vibration and transient events from material research and industrial applications are presented. The results show typical features of the system.

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

    PubMed

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

    2017-09-08

    The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M(pro)) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M(pro) significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M(pro). These novel compounds displayed excellent IC50 data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. On 3-D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Todd, E. S.

    1986-01-01

    The objective of this program is to produce a series of new computer codes that permit more accurate and efficient three-dimensional inelastic structural analysis of combustor liners, turbine blades, and turbine vanes. Each code embodies a progression of mathematical models for increasingly comprehensive representation of the geometrical features, loading conditions, and forms of nonlinear material response that distinguish these three groups of hot section components.

  3. 3D visualization and quantitative analysis of human erythrocyte phagocytosis.

    PubMed

    Stachurska, Anna; Król, Teodora; Trybus, Wojciech; Szary, Karol; Fabijańska-Mitek, Jadwiga

    2016-11-01

    Since the erythrophagocytosis of opsonized erythrocytes is investigated mainly by calculating the phagocytic index using subjective light microscopy evaluation, we present methods for the quantitative and qualitative analysis of human cell erythrophagocytosis. Erythrocytes from two storage periods were used. Using Imaris software, we were able to create a three-dimensional model of erythrophagocytosis. The use of microscopy instead of cytometry revealed a significantly higher number of monocytes and erythrocytes that appeared active in phagocytosis. Spatial reconstruction allowed for detailed analysis of the process by precisely locating erythrocytes in phagocytes. Additionally, a technique of sequential image registration using Nis Elements software allowed for observation of the course of phagocytosis over a range of time intervals. This in vitro research may be helpful for understanding the cellular interactions between monocytes and erythrocytes. The cytometric method-being relatively rapid, sensitive, and specific-can serve as an alternative technique to microscopy in the quantitative analysis of erythrophagocytosis. This allows us to avoid counting the erythrocytes nonspecifically attached to monocytes and gives objective results. © 2016 International Federation for Cell Biology.

  4. 3D neutronic/thermal-hydraulic coupled analysis of MYRRHA

    SciTech Connect

    Vazquez, M.; Martin-Fuertes, F.

    2012-07-01

    The current tendency in multiphysics calculations applied to reactor physics is the use of already validated computer codes, coupled by means of an iterative approach. In this paper such an approach is explained concerning neutronics and thermal-hydraulics coupled analysis with MCNPX and COBRA-IV codes using a driver program and file exchange between codes. MCNPX provides the neutronic analysis of heterogeneous nuclear systems, both in critical and subcritical states, while COBRA-IV is a subchannel code that can be used for rod bundles or core thermal-hydraulics analysis. In our model, the MCNP temperature dependence of nuclear data is handled via pseudo-material approach, mixing pre-generated cross section data set to obtain the material with the desired cross section temperature. On the other hand, COBRA-IV has been updated to allow for the simulation of liquid metal cooled reactors. The coupled computational tool can be applied to any geometry and coolant, as it is the case of single fuel assembly, at pin-by-pin level, or full core simulation with the average pin of each fuel-assembly. The coupling tool has been applied to the critical core layout of the SCK-CEN MYRRHA concept, an experimental LBE cooled fast reactor presently in engineering design stage. (authors)

  5. A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs.

    PubMed

    Lee, Sehan; Barron, Mace G

    2016-04-01

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π-π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency.

  6. A mechanism-based 3D-QSAR approach for classification and prediction of acetylcholinesterase inhibitory potency of organophosphate and carbamate analogs

    NASA Astrophysics Data System (ADS)

    Lee, Sehan; Barron, Mace G.

    2016-04-01

    Organophosphate (OP) and carbamate esters can inhibit acetylcholinesterase (AChE) by binding covalently to a serine residue in the enzyme active site, and their inhibitory potency depends largely on affinity for the enzyme and the reactivity of the ester. Despite this understanding, there has been no mechanism-based in silico approach for classification and prediction of the inhibitory potency of ether OPs or carbamates. This prompted us to develop a three dimensional prediction framework for OPs, carbamates, and their analogs. Inhibitory structures of a compound that can form the covalent bond were identified through analysis of docked conformations of the compound and its metabolites. Inhibitory potencies of the selected structures were then predicted using a previously developed three dimensional quantitative structure-active relationship. This approach was validated with a large number of structurally diverse OP and carbamate compounds encompassing widely used insecticides and structural analogs including OP flame retardants and thio- and dithiocarbamate pesticides. The modeling revealed that: (1) in addition to classical OP metabolic activation, the toxicity of carbamate compounds can be dependent on biotransformation, (2) OP and carbamate analogs such as OP flame retardants and thiocarbamate herbicides can act as AChEI, (3) hydrogen bonds at the oxyanion hole is critical for AChE inhibition through the covalent bond, and (4) π-π interaction with Trp86 is necessary for strong inhibition of AChE. Our combined computation approach provided detailed understanding of the mechanism of action of OP and carbamate compounds and may be useful for screening a diversity of chemical structures for AChE inhibitory potency.

  7. Reducing Non-Uniqueness in Satellite Gravity Inversion using 3D Object Oriented Image Analysis Techniques

    NASA Astrophysics Data System (ADS)

    Fadel, I.; van der Meijde, M.; Kerle, N.

    2013-12-01

    Non-uniqueness of satellite gravity interpretation has been usually reduced by using a priori information from various sources, e.g. seismic tomography models. The reduction in non-uniqueness has been based on velocity-density conversion formulas or user interpretation for 3D subsurface structures (objects) in seismic tomography models. However, these processes introduce additional uncertainty through the conversion relations due to the dependency on the other physical parameters such as temperature and pressure, or through the bias in the interpretation due to user choices and experience. In this research, a new methodology is introduced to extract the 3D subsurface structures from 3D geophysical data using a state-of-art 3D Object Oriented Image Analysis (OOA) technique. 3D OOA is tested using a set of synthetic models that simulate the real situation in the study area of this research. Then, 3D OOA is used to extract 3D subsurface objects from a real 3D seismic tomography model. The extracted 3D objects are used to reconstruct a forward model and its response is compared with the measured satellite gravity. Finally, the result of the forward modelling, based on the extracted 3D objects, is used to constrain the inversion process of satellite gravity data. Through this work, a new object-based approach is introduced to interpret and extract the 3D subsurface objects from 3D geophysical data. This can be used to constrain modelling and inversion of potential field data using the extracted 3D subsurface structures from other methods. In summary, a new approach is introduced to constrain inversion of satellite gravity measurements and enhance interpretation capabilities.

  8. 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.

  9. 2D-to-3D conversion by using visual attention analysis

    NASA Astrophysics Data System (ADS)

    Kim, Jiwon; Baik, Aron; Jung, Yong Ju; Park, Dusik

    2010-02-01

    This paper proposes a novel 2D-to-3D conversion system based on visual attention analysis. The system was able to generate stereoscopic video from monocular video in a robust manner with no human intervention. According to our experiment, visual attention information can be used to provide rich 3D experience even when depth cues from monocular view are not enough. Using the algorithm introduced in the paper, 3D display users can watch 2D media in 3D. In addition, the algorithm can be embedded into 3D displays in order to deliver better viewing experience with more immersive feeling. Using visual attention information to give a 3D effect is first tried in this research as far as we know.

  10. An optical real-time 3D measurement for analysis of facial shape and movement

    NASA Astrophysics Data System (ADS)

    Zhang, Qican; Su, Xianyu; Chen, Wenjing; Cao, Yiping; Xiang, Liqun

    2003-12-01

    Optical non-contact 3-D shape measurement provides a novel and useful tool for analysis of facial shape and movement in presurgical and postsurgical regular check. In this article we present a system, which allows a precise 3-D visualization of the patient's facial before and after craniofacial surgery. We discussed, in this paper, the real time 3-D image capture, processing and the 3-D phase unwrapping method to recover complex shape deformation when the movement of the mouth. The result of real-time measurement for facial shape and movement will be helpful for the more ideal effect in plastic surgery.

  11. 3D inelastic analysis methods for hot section components

    NASA Technical Reports Server (NTRS)

    Dame, L. T.; Chen, P. C.; Hartle, M. S.; Huang, H. T.

    1985-01-01

    The objective is to develop analytical tools capable of economically evaluating the cyclic time dependent plasticity which occurs in hot section engine components in areas of strain concentration resulting from the combination of both mechanical and thermal stresses. Three models were developed. A simple model performs time dependent inelastic analysis using the power law creep equation. The second model is the classical model of Professors Walter Haisler and David Allen of Texas A and M University. The third model is the unified model of Bodner, Partom, et al. All models were customized for linear variation of loads and temperatures with all material properties and constitutive models being temperature dependent.

  12. High Resolution Krylov Space 3-D Wavenumber-Frequency Analysis

    DTIC Science & Technology

    2007-04-01

    wavenumber-frequency distri- bution of signal modes. That is, PPER (k, f, t) = eH(k) R̂[f, t] e(k). (3) Different from eq.(2), here R̂[f, t] is a time... PPER (k, f, t) frequency f w av en um be r k Capon wavenumber frequency analysis 0.4 0.5 0.6 0.7 0.8 0.9 1 0.5 0.4 0.3 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 30

  13. Vector algorithms for geometrically nonlinear 3D finite element analysis

    NASA Technical Reports Server (NTRS)

    Whitcomb, John D.

    1989-01-01

    Algorithms for geometrically nonlinear finite element analysis are presented which exploit the vector processing capability of the VPS-32, which is closely related to the CYBER 205. By manipulating vectors (which are long lists of numbers) rather than individual numbers, very high processing speeds are obtained. Long vector lengths are obtained without extensive replication or reordering by storage of intermediate results in strategic patterns at all stages of the computations. Comparisons of execution times with those from programs using either scalar or other vector programming techniques indicate that the algorithms presented are quite efficient.

  14. Multiscale 3D Shape Analysis using Spherical Wavelets

    PubMed Central

    Nain, Delphine; Haker, Steven; Bobick, Aaron; Tannenbaum, Allen

    2013-01-01

    Shape priors attempt to represent biological variations within a population. When variations are global, Principal Component Analysis (PCA) can be used to learn major modes of variation, even from a limited training set. However, when significant local variations exist, PCA typically cannot represent such variations from a small training set. To address this issue, we present a novel algorithm that learns shape variations from data at multiple scales and locations using spherical wavelets and spectral graph partitioning. Our results show that when the training set is small, our algorithm significantly improves the approximation of shapes in a testing set over PCA, which tends to oversmooth data. PMID:16685992

  15. Multiscale 3D shape analysis using spherical wavelets.

    PubMed

    Nain, Delphine; Haker, Steven; Bobick, Aaron; Tannenbaum, Allen R

    2005-01-01

    Shape priors attempt to represent biological variations within a population. When variations are global, Principal Component Analysis (PCA) can be used to learn major modes of variation, even from a limited training set. However, when significant local variations exist, PCA typically cannot represent such variations from a small training set. To address this issue, we present a novel algorithm that learns shape variations from data at multiple scales and locations using spherical wavelets and spectral graph partitioning. Our results show that when the training set is small, our algorithm significantly improves the approximation of shapes in a testing set over PCA, which tends to oversmooth data.

  16. 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.

  17. Evaluation of stereoscopic 3D displays for image analysis tasks

    NASA Astrophysics Data System (ADS)

    Peinsipp-Byma, E.; Rehfeld, N.; Eck, R.

    2009-02-01

    In many application domains the analysis of aerial or satellite images plays an important role. The use of stereoscopic display technologies can enhance the image analyst's ability to detect or to identify certain objects of interest, which results in a higher performance. Changing image acquisition from analog to digital techniques entailed the change of stereoscopic visualisation techniques. Recently different kinds of digital stereoscopic display techniques with affordable prices have appeared on the market. At Fraunhofer IITB usability tests were carried out to find out (1) with which kind of these commercially available stereoscopic display techniques image analysts achieve the best performance and (2) which of these techniques achieve a high acceptance. First, image analysts were interviewed to define typical image analysis tasks which were expected to be solved with a higher performance using stereoscopic display techniques. Next, observer experiments were carried out whereby image analysts had to solve defined tasks with different visualization techniques. Based on the experimental results (performance parameters and qualitative subjective evaluations of the used display techniques) two of the examined stereoscopic display technologies were found to be very good and appropriate.

  18. Sub aquatic 3D visualization and temporal analysis utilizing ArcGIS online and 3D applications

    EPA Science Inventory

    We used 3D Visualization tools to illustrate some complex water quality data we’ve been collecting in the Great Lakes. These data include continuous tow data collected from our research vessel the Lake Explorer II, and continuous water quality data collected from an autono...

  19. 3D site specific sample preparation and analysis of 3D devices (FinFETs) by atom probe tomography.

    PubMed

    Kambham, Ajay Kumar; Kumar, Arul; Gilbert, Matthieu; Vandervorst, Wilfried

    2013-09-01

    With the transition from planar to three-dimensional device architectures such as Fin field-effect-transistors (FinFETs), new metrology approaches are required to meet the needs of semiconductor technology. It is important to characterize the 3D-dopant distributions precisely as their extent, positioning relative to gate edges and absolute concentration determine the device performance in great detail. At present the atom probe has shown its ability to analyze dopant distributions in semiconductor and thin insulating materials with sub-nm 3D-resolution and good dopant sensitivity. However, so far most reports have dealt with planar devices or restricted the measurements to 2D test structures which represent only limited challenges in terms of localization and site specific sample preparation. In this paper we will discuss the methodology to extract the dopant distribution from real 3D-devices such as a 3D-FinFET device, requiring the sample preparation to be carried out at a site specific location with a positioning accuracy ∼50 nm. Copyright © 2013 Elsevier B.V. All rights reserved.

  20. Sub aquatic 3D visualization and temporal analysis utilizing ArcGIS online and 3D applications

    EPA Science Inventory

    We used 3D Visualization tools to illustrate some complex water quality data we’ve been collecting in the Great Lakes. These data include continuous tow data collected from our research vessel the Lake Explorer II, and continuous water quality data collected from an autono...

  1. Galerkin Boundary Integral Analysis for the 3D Helmholtz Equation

    SciTech Connect

    Swager, Melissa; Gray, Leonard J; Nintcheu Fata, Sylvain

    2010-01-01

    A linear element Galerkin boundary integral analysis for the three-dimensional Helmholtz equation is presented. The emphasis is on solving acoustic scattering by an open (crack) surface, and to this end both a dual equation formulation and a symmetric hypersingular formulation have been developed. All singular integrals are defined and evaluated via a boundary limit process, facilitating the evaluation of the (finite) hypersingular Galerkin integral. This limit process is also the basis for the algorithm for post-processing of the surface gradient. The analytic integrations required by the limit process are carried out by employing a Taylor series expansion for the exponential factor in the Helmholtz fundamental solutions. For the open surface, the implementations are validated by comparing the numerical results obtained by using the two different methods.

  2. 3D Reacting Flow Analysis of LANTR Nozzles

    NASA Astrophysics Data System (ADS)

    Stewart, Mark E. M.; Krivanek, Thomas M.; Hemminger, Joseph A.; Bulman, M. J.

    2006-01-01

    This paper presents performance predictions for LANTR nozzles and the system implications for their use in a manned Mars mission. The LANTR concept is rocket thrust augmentation by injecting Oxygen into the nozzle to combust the Hydrogen exhaust of a Nuclear Thermal Rocket. The performance predictions are based on three-dimensional reacting flow simulations using VULCAN. These simulations explore a range of O2/H2 mixture ratios, injector configurations, and concepts. These performance predictions are used for a trade analysis within a system study for a manned Mars mission. Results indicate that the greatest benefit of LANTR will occur with In-Situ Resource Utilization (ISRU). However, Hydrogen propellant volume reductions may allow greater margins for fitting tanks within the launch vehicle where packaging issues occur.

  3. Modeling and analysis of 3-D elongated shapes with applications to long bone morphometry

    SciTech Connect

    Burdin, V.; Roux, C.; Lefevre, C.; Stindel, E.

    1996-02-01

    This paper presents a geometric model to be used as a framework for the description and analysis of three-dimensional (3-D) elongated shapes. Elongated shapes can be decomposed into two different parts: a 3-D curve (the central axis) and a 3-D surface (the straight surface). The central axis is described in terms of curvature and torsion. A novel concept of torsion image is introduced which allows the user to study the torsion of some relevant 3-D structures such as the medulla of long bones, without computing the third derivative. The description of the straight surface is based on an ordered set of Fourier Descriptors (FD`s), each set representing a 2-D slice of the structure. These descriptors possess completeness, continuity, and stability properties, and some geometrical invariancies. A polar diagram is built which contains the anatomical information of the straight surface and can be used as a tool for the analysis and discrimination of 3-D structures. A technique for the reconstruction of the 3-D surface from the model`s two components is presented. Various applications to the analysis of long bone structures, such as the ulna and radius, are derived from the model, namely, data compression, comparison of 3-D shapes, segmentation into 3-D primitives, and torsion and curvature analysis. The relevance of the method to morphometry and to clinical applications is discussed.

  4. Code System for Analysis of 3-D Reinforced Concrete Structures.

    SciTech Connect

    ANDERSON, C. A.

    1999-11-22

    Version 00 NONSAP-C is a finite element program for determining the static and dynamic response of three-dimensional reinforced concrete structures. Long-term, or creep, behavior of concrete structures can also be analyzed. Nonlinear constitutive relations for concrete under short-term loads are incorporated in two time-independent models, a variable-modulus approach with orthotropic behavior induced in the concrete due to the development of different tangent moduli in different directions and an elastic-plastic model in which the concrete is assumed to be a continuous, isotropic, and linearly elastic-plastic strain-hardening-fracture material. A viscoelastic constitutive model for long-term thermal creep of concrete is included. Three-dimensional finite elements available in NONSAP-C include a truss element, a multinode tendon element for prestressed and post tensioned concrete structures, an elastic-plastic membrane element to represent the behavior of cavity liners, and a general isoparametric element with a variable number of nodes for analysis of solids and thick shells.

  5. Role of moving average analysis for development of multi-target (Q)SAR models.

    PubMed

    Khatri, N; Dutt, R; Madan, A K

    2015-01-01

    In modern drug discovery era, multi target- quantitative structure activity relationship [mt- (Q)SAR] approaches have emerged as novel and powerful alternatives in the field of in-silico drug design so as to facilitate the discovery of new chemical entities with multiple biological activities. Amongst various machine learning approaches, moving average analysis (MAA) has frequently exhibited high accuracy of prediction of diverse biological activities against different biological targets and experimental conditions. Role of MAA in developing (Q)SAR models for prediction of single/dual or multi target activity has been briefly reviewed in the present article. Subsequently, MAA was successfully utilized for developing mt-(Q)SAR models for simultaneous prediction of anti-Plasmodium falciparum and anti-Trypanosoma brucei rhodesiense activities of benzyl phenyl ether derivatives. The statistical significance of models was assessed through intercorrelation analysis, sensitivity, specificity and Matthew's correlation coefficient. Proposed MAA based models were also validated using test set. High predictability of the order of 80% to 95% amalgamated with safety (indicated by high value of selectivity index) of proposed mt-(Q)SAR models justifies use of MAA in developing models in order to obtain more realistic and accurate results for prediction of anti-protozal activity against multiple targets. Active ranges of the proposed models can play a significant role in the development of novel, potent, versatile and safe anti-protozoal drugs with improved profile in terms of both anti-Plasmodium falciparum and anti-Trypanosoma brucei rhodesiense activities.

  6. Implementation of SEREP Into LLNL Dyna3d for Global/Local Analysis

    DTIC Science & Technology

    2005-08-01

    Implementation of SEREP Into LLNL Dyna3d for Global/Local Analysis by David A. Hopkins and Michael A. Minnicino II ARL-TR-3569 August...2005 Implementation of SEREP Into LLNL Dyna3d for Global/Local Analysis David A. Hopkins and Michael A. Minnicino II Weapons and...LLNL Dyna3d for Global/Local Analysis 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 622618H80 5e. TASK NUMBER 6. AUTHOR(S) David A. Hopkins

  7. CheS-Mapper 2.0 for visual validation of (Q)SAR models

    PubMed Central

    2014-01-01

    Background Sound statistical validation is important to evaluate and compare the overall performance of (Q)SAR models. However, classical validation does not support the user in better understanding the properties of the model or the underlying data. Even though, a number of visualization tools for analyzing (Q)SAR information in small molecule datasets exist, integrated visualization methods that allow the investigation of model validation results are still lacking. Results We propose visual validation, as an approach for the graphical inspection of (Q)SAR model validation results. The approach applies the 3D viewer CheS-Mapper, an open-source application for the exploration of small molecules in virtual 3D space. The present work describes the new functionalities in CheS-Mapper 2.0, that facilitate the analysis of (Q)SAR information and allows the visual validation of (Q)SAR models. The tool enables the comparison of model predictions to the actual activity in feature space. The approach is generic: It is model-independent and can handle physico-chemical and structural input features as well as quantitative and qualitative endpoints. Conclusions Visual validation with CheS-Mapper enables analyzing (Q)SAR information in the data and indicates how this information is employed by the (Q)SAR model. It reveals, if the endpoint is modeled too specific or too generic and highlights common properties of misclassified compounds. Moreover, the researcher can use CheS-Mapper to inspect how the (Q)SAR model predicts activity cliffs. The CheS-Mapper software is freely available at http://ches-mapper.org. Graphical abstract Comparing actual and predicted activity values with CheS-Mapper.

  8. Advanced Visualization and Analysis of Climate Data using DV3D and UV-CDAT

    NASA Astrophysics Data System (ADS)

    Maxwell, T. P.

    2012-12-01

    This paper describes DV3D, a Vistrails package of high-level modules for the Ultra-scale Visualization Climate Data Analysis Tools (UV-CDAT) interactive visual exploration system that enables exploratory analysis of diverse and rich data sets stored in the Earth System Grid Federation (ESGF). DV3D provides user-friendly workflow interfaces for advanced visualization and analysis of climate data at a level appropriate for scientists. The application builds on VTK, an open-source, object-oriented library, for visualization and analysis. DV3D provides the high-level interfaces, tools, and application integrations required to make the analysis and visualization power of VTK readily accessible to users without exposing burdensome details such as actors, cameras, renderers, and transfer functions. It can run as a desktop application or distributed over a set of nodes for hyperwall or distributed visualization applications. DV3D is structured as a set of modules which can be linked to create workflows in Vistrails. Figure 1 displays a typical DV3D workflow as it would appear in the Vistrails workflow builder interface of UV-CDAT and, on the right, the visualization spreadsheet output of the workflow. Each DV3D module encapsulates a complex VTK pipeline with numerous supporting objects. Each visualization module implements a unique interactive 3D display. The integrated Vistrails visualization spreadsheet offers multiple synchronized visualization displays for desktop or hyperwall. The currently available displays include volume renderers, volume slicers, 3D isosurfaces, 3D hovmoller, and various vector plots. The DV3D GUI offers a rich selection of interactive query, browse, navigate, and configure options for all displays. All configuration operations are saved as Vistrails provenance. DV3D's seamless integration with UV-CDAT's climate data management system (CDMS) and other climate data analysis tools provides a wide range of climate data analysis operations, e

  9. IMPROMPTU: a system for automatic 3D medical image-analysis.

    PubMed

    Sundaramoorthy, G; Hoford, J D; Hoffman, E A; Higgins, W E

    1995-01-01

    The utility of three-dimensional (3D) medical imaging is hampered by difficulties in extracting anatomical regions and making measurements in 3D images. Presently, a user is generally forced to use time-consuming, subjective, manual methods, such as slice tracing and region painting, to define regions of interest. Automatic image-analysis methods can ameliorate the difficulties of manual methods. This paper describes a graphical user interface (GUI) system for constructing automatic image-analysis processes for 3D medical-imaging applications. The system, referred to as IMPROMPTU, provides a user-friendly environment for prototyping, testing and executing complex image-analysis processes. IMPROMPTU can stand alone or it can interact with an existing graphics-based 3D medical image-analysis package (VIDA), giving a strong environment for 3D image-analysis, consisting of tools for visualization, manual interaction, and automatic processing. IMPROMPTU links to a large library of 1D, 2D, and 3D image-processing functions, referred to as VIPLIB, but a user can easily link in custom-made functions. 3D applications of the system are given for left-ventricular chamber, myocardial, and upper-airway extractions.

  10. QSAR studies on imidazopyrazine derivatives as Aurora A kinase inhibitors.

    PubMed

    Leng, Y; Lu, T; Yuan, H L; Liu, H C; Lu, S; Zhang, W W; Jiang, Y L; Chen, Y D

    2012-10-01

    Aurora kinases have emerged as attractive targets for the development of novel anti-cancer agents. A combined study of molecular docking, pharmacophore modelling and 3D-QSAR was performed on a series of imidazo [1, 2-a] pyrazines as novel Aurora kinase inhibitors to gain insights into the structural determinants and their structure-activity relationship. An ensemble of conformations based on molecular docking was used for PHASE pharmacophore studies. The developed best-fitted pharmacophore model was validated by diverse chemotypes of Aurora A kinase inhibitors and was consistent with the structural requirements for the docked binding mechanism. Subsequently, the pharmacophore-based alignment was used to develop PHASE and comparative molecular similarity indices analysis (CoMSIA) 3D-QSAR models. The best CoMSIA model showed good statistics (q (2 )= 0.567, r (2 )= 0.992), and the predictive ability of the model was validated using an external test set of 13 compounds giving a satisfactory prediction ([Formula: see text]). The 3D contour maps provided insight into the binding mechanism and highlighted key structural features that are essential to the inhibitory activity. Based on the PHASE and CoMSIA 3D-QSAR results, a set of novel Aurora A inhibitors were designed that showed excellent potencies.

  11. 3D Building Models Segmentation Based on K-Means++ Cluster Analysis

    NASA Astrophysics Data System (ADS)

    Zhang, C.; Mao, B.

    2016-10-01

    3D mesh model segmentation is drawing increasing attentions from digital geometry processing field in recent years. The original 3D mesh model need to be divided into separate meaningful parts or surface patches based on certain standards to support reconstruction, compressing, texture mapping, model retrieval and etc. Therefore, segmentation is a key problem for 3D mesh model segmentation. In this paper, we propose a method to segment Collada (a type of mesh model) 3D building models into meaningful parts using cluster analysis. Common clustering methods segment 3D mesh models by K-means, whose performance heavily depends on randomized initial seed points (i.e., centroid) and different randomized centroid can get quite different results. Therefore, we improved the existing method and used K-means++ clustering algorithm to solve this problem. Our experiments show that K-means++ improves both the speed and the accuracy of K-means, and achieve good and meaningful results.

  12. User's Manual for DuctE3D: A Program for 3D Euler Unsteady Aerodynamic and Aeroelastic Analysis of Ducted Fans

    NASA Technical Reports Server (NTRS)

    Srivastava, R.; Reddy, T. S. R.

    1997-01-01

    The program DuctE3D is used for steady or unsteady aerodynamic and aeroelastic analysis of ducted fans. This guide describes the input data required and the output files generated, in using DuctE3D. The analysis solves three dimensional unsteady, compressible Euler equations to obtain the aerodynamic forces. A normal mode structural analysis is used to obtain the aeroelastic equations, which are solved using either the time domain or the frequency domain solution method. Sample input and output files are included in this guide for steady aerodynamic analysis and aeroelastic analysis of an isolated fan row.

  13. Effects of multiple conformers per compound upon 3-D similarity search and bioassay data analysis

    PubMed Central

    2012-01-01

    Background To improve the utility of PubChem, a public repository containing biological activities of small molecules, the PubChem3D project adds computationally-derived three-dimensional (3-D) descriptions to the small-molecule records contained in the PubChem Compound database and provides various search and analysis tools that exploit 3-D molecular similarity. Therefore, the efficient use of PubChem3D resources requires an understanding of the statistical and biological meaning of computed 3-D molecular similarity scores between molecules. Results The present study investigated effects of employing multiple conformers per compound upon the 3-D similarity scores between ten thousand randomly selected biologically-tested compounds (10-K set) and between non-inactive compounds in a given biological assay (156-K set). When the “best-conformer-pair” approach, in which a 3-D similarity score between two compounds is represented by the greatest similarity score among all possible conformer pairs arising from a compound pair, was employed with ten diverse conformers per compound, the average 3-D similarity scores for the 10-K set increased by 0.11, 0.09, 0.15, 0.16, 0.07, and 0.18 for STST-opt, CTST-opt, ComboTST-opt, STCT-opt, CTCT-opt, and ComboTCT-opt, respectively, relative to the corresponding averages computed using a single conformer per compound. Interestingly, the best-conformer-pair approach also increased the average 3-D similarity scores for the non-inactive–non-inactive (NN) pairs for a given assay, by comparable amounts to those for the random compound pairs, although some assays showed a pronounced increase in the per-assay NN-pair 3-D similarity scores, compared to the average increase for the random compound pairs. Conclusion These results suggest that the use of ten diverse conformers per compound in PubChem bioassay data analysis using 3-D molecular similarity is not expected to increase the separation of non-inactive from random and inactive

  14. In silico evaluation, molecular docking and QSAR analysis of quinazoline-based EGFR-T790M inhibitors.

    PubMed

    Asadollahi-Baboli, M

    2016-08-01

    Mutated epidermal growth factor receptor (EGFR-T790M) inhibitors hold promise as new agents against cancer. Molecular docking and QSAR analysis were performed based on a series of fifty-three quinazoline derivatives to elucidate key structural and physicochemical properties affecting inhibitory activity. Molecular docking analysis identified the true conformations of ligands in the receptor's active pocket. The structural features of the ligands, expressed as molecular descriptors, were derived from the obtained docked conformations. Non-linear and spline QSAR models were developed through novel genetic algorithm and artificial neural network (GA-ANN) and multivariate adaptive regression spline techniques, respectively. The former technique was employed to consider non-linear relation between molecular descriptors and inhibitory activity of quinazoline derivatives. The later technique was also used to describe the non-linearity using basis functions and sub-region equations for each descriptor. Our QSAR model gave a high predictive performance [Formula: see text] and [Formula: see text]) using diverse validation techniques. Eight new compounds were designed using our QSAR model as potent EGFR-T790M inhibitors. Overall, the proposed in silico strategy based on docked derived descriptor and non-linear descriptor subset selection may help design novel quinazoline derivatives with improved EGFR-T790M inhibitory activity.

  15. 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.

  16. QSAR Analysis of Some Antagonists for p38 map kinase Using Combination of Principal Component Analysis and Artificial Intelligence.

    PubMed

    Doosti, Elham; Shahlaei, Mohsen

    2015-01-01

    Quantitative relationships between structures of a set of p38 map kinase inhibitors and their activities were investigated by principal component regression (PCR) and principal componentartificial neural network (PC-ANN). Latent variables (called components) generated by principal component analysis procedure were applied as the input of developed Quantitative structure- activity relationships (QSAR) models. An exact study of predictability of PCR and PC-ANN showed that the later model has much higher ability to calculate the biological activity of the investigated molecules. Also, experimental and estimated biological activities of compounds used in model development step have indicated a good correlation. Obtained results show that a non-linear model explaining the relationship between the pIC50s and the calculated principal components (that extract from structural descriptors of the studied molecules) is superior than linear model. Some typical figures of merit for QSAR studies explaining the accuracy and predictability of the suggested models were calculated. Therefore, to design novel inhibitors of p38 map kinase with high potency and low undesired effects the developed QSAR models were used to estimate biological pIC50 of the studied compounds.

  17. The 3D Tele Motion Tracking for the Orthodontic Facial Analysis

    PubMed Central

    Nota, Alessandro; Marchetti, Enrico; Padricelli, Giuseppe; Marzo, Giuseppe

    2016-01-01

    Aim. This study aimed to evaluate the reliability of 3D-TMT, previously used only for dynamic testing, in a static cephalometric evaluation. Material and Method. A group of 40 patients (20 males and 20 females; mean age 14.2 ± 1.2 years; 12–18 years old) was included in the study. The measurements obtained by the 3D-TMT cephalometric analysis with a conventional frontal cephalometric analysis were compared for each subject. Nine passive markers reflectors were positioned on the face skin for the detection of the profile of the patient. Through the acquisition of these points, corresponding plans for three-dimensional posterior-anterior cephalometric analysis were found. Results. The cephalometric results carried out with 3D-TMT and with traditional posterior-anterior cephalometric analysis showed the 3D-TMT system values are slightly higher than the values measured on radiographs but statistically significant; nevertheless their correlation is very high. Conclusion. The recorded values obtained using the 3D-TMT analysis were correlated to cephalometric analysis, with small but statistically significant differences. The Dahlberg errors resulted to be always lower than the mean difference between the 2D and 3D measurements. A clinician should use, during the clinical monitoring of a patient, always the same method, to avoid comparing different millimeter magnitudes. PMID:28044130

  18. 3D shape analysis for early diagnosis of malignant lung nodules.

    PubMed

    El-Baz, Ayman; Nitzken, Matthew; Elnakib, Ahmed; Khalifa, Fahmi; Gimel'farb, Georgy; Falk, Robert; El-Ghar, Mohamed Abou

    2011-01-01

    An alternative method of diagnosing malignant lung nodules by their shape, rather than conventional growth rate, is proposed. The 3D surfaces of the detected lung nodules are delineated by spherical harmonic analysis that represents a 3D surface of the lung nodule supported by the unit sphere with a linear combination of special basis functions, called Spherical Harmonics (SHs). The proposed 3D shape analysis is carried out in five steps: (i) 3D lung nodule segmentation with a deformable 3D boundary controlled by a new prior visual appearance model; (ii) 3D Delaunay triangulation to construct a 3D mesh model of the segmented lung nodule surface; (iii) mapping this model to the unit sphere; (iv) computing the SHs for the surface; and (v) determining the number of the SHs to delineate the lung nodule. We describe the lung nodule shape complexity with a new shape index, the estimated number of the SHs, and use it for the K-nearest classification into malignant and benign lung nodules. Preliminary experiments on 327 lung nodules (153 malignant and 174 benign) resulted in a classification accuracy of 93.6%, showing that the proposed method is a promising supplement to current technologies for the early diagnosis of lung cancer.

  19. 3D shape analysis for early diagnosis of malignant lung nodules.

    PubMed

    El-Bazl, Ayman; Nitzken, Matthew; Khalifa, Fahmi; Elnakib, Ahmed; Gimel'farb, Georgy; Falk, Robert; El-Ghar, Mohammed Abo

    2011-01-01

    An alternative method for diagnosing malignant lung nodules by their shape rather than conventional growth rate is proposed. The 3D surfaces of the detected lung nodules are delineated by spherical harmonic analysis, which represents a 3D surface of the lung nodule supported by the unit sphere with a linear combination of special basis functions, called spherical harmonics (SHs). The proposed 3D shape analysis is carried out in five steps: (i) 3D lung nodule segmentation with a deformable 3D boundary controlled by two probabilistic visual appearance models (the learned prior and the estimated current appearance one); (ii) 3D Delaunay triangulation to construct a 3D mesh model of the segmented lung nodule surface; (iii) mapping this model to the unit sphere; (iv) computing the SHs for the surface, and (v) determining the number of the SHs to delineate the lung nodule. We describe the lung nodule shape complexity with a new shape index, the estimated number of the SHs, and use it for the K-nearest classification to distinguish malignant and benign lung nodules. Preliminary experiments on 327 lung nodules (153 malignant and 174 benign) resulted in the 93.6% correct classification (for the 95% confidence interval), showing that the proposed method is a promising supplement to current technologies for the early diagnosis of lung cancer.

  20. Automated Quantification and Integrative Analysis of 2D and 3D Mitochondrial Shape and Network Properties

    PubMed Central

    Nikolaisen, Julie; Nilsson, Linn I. H.; Pettersen, Ina K. N.; Willems, Peter H. G. M.; Lorens, James B.; Koopman, Werner J. H.; Tronstad, Karl J.

    2014-01-01

    Mitochondrial morphology and function are coupled in healthy cells, during pathological conditions and (adaptation to) endogenous and exogenous stress. In this sense mitochondrial shape can range from small globular compartments to complex filamentous networks, even within the same cell. Understanding how mitochondrial morphological changes (i.e. “mitochondrial dynamics”) are linked to cellular (patho) physiology is currently the subject of intense study and requires detailed quantitative information. During the last decade, various computational approaches have been developed for automated 2-dimensional (2D) analysis of mitochondrial morphology and number in microscopy images. Although these strategies are well suited for analysis of adhering cells with a flat morphology they are not applicable for thicker cells, which require a three-dimensional (3D) image acquisition and analysis procedure. Here we developed and validated an automated image analysis algorithm allowing simultaneous 3D quantification of mitochondrial morphology and network properties in human endothelial cells (HUVECs). Cells expressing a mitochondria-targeted green fluorescence protein (mitoGFP) were visualized by 3D confocal microscopy and mitochondrial morphology was quantified using both the established 2D method and the new 3D strategy. We demonstrate that both analyses can be used to characterize and discriminate between various mitochondrial morphologies and network properties. However, the results from 2D and 3D analysis were not equivalent when filamentous mitochondria in normal HUVECs were compared with circular/spherical mitochondria in metabolically stressed HUVECs treated with rotenone (ROT). 2D quantification suggested that metabolic stress induced mitochondrial fragmentation and loss of biomass. In contrast, 3D analysis revealed that the mitochondrial network structure was dissolved without affecting the amount and size of the organelles. Thus, our results demonstrate that 3D

  1. QSAR modeling and chemical space analysis of antimalarial compounds

    NASA Astrophysics Data System (ADS)

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-05-01

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including 3000 molecules tested in one or several of 17 anti- Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  2. QSAR modeling and chemical space analysis of antimalarial compounds.

    PubMed

    Sidorov, Pavel; Viira, Birgit; Davioud-Charvet, Elisabeth; Maran, Uko; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

    2017-04-03

    Generative topographic mapping (GTM) has been used to visualize and analyze the chemical space of antimalarial compounds as well as to build predictive models linking structure of molecules with their antimalarial activity. For this, a database, including ~3000 molecules tested in one or several of 17 anti-Plasmodium activity assessment protocols, has been compiled by assembling experimental data from in-house and ChEMBL databases. GTM classification models built on subsets corresponding to individual bioassays perform similarly to the earlier reported SVM models. Zones preferentially populated by active and inactive molecules, respectively, clearly emerge in the class landscapes supported by the GTM model. Their analysis resulted in identification of privileged structural motifs of potential antimalarial compounds. Projection of marketed antimalarial drugs on this map allowed us to delineate several areas in the chemical space corresponding to different mechanisms of antimalarial activity. This helped us to make a suggestion about the mode of action of the molecules populating these zones.

  3. Analysis of the 3D distribution of stacked self-assembled quantum dots by electron tomography

    PubMed Central

    2012-01-01

    The 3D distribution of self-assembled stacked quantum dots (QDs) is a key parameter to obtain the highest performance in a variety of optoelectronic devices. In this work, we have measured this distribution in 3D using a combined procedure of needle-shaped specimen preparation and electron tomography. We show that conventional 2D measurements of the distribution of QDs are not reliable, and only 3D analysis allows an accurate correlation between the growth design and the structural characteristics. PMID:23249477

  4. Multiresolution analysis of 3D multimodal objects using a 2D quincunx wavelet analysis

    NASA Astrophysics Data System (ADS)

    Toubin, Marc F.; Dumont, Christophe; Truchetet, Frederic; Abidi, Mongi A.

    1999-08-01

    A reconstructed scene in virtual reality typically consists of millions of triangles.Data are heterogeneous and consist not only of geometric coordinates but also of multi-modal data. The latter requires more complex calculations and very high-speed graphics. Due to the large amount of data, displaying and analyzing these 3D models require new methods. This paper present an innovative method to analyze multi-model models using a 2D-quincunx wavelet analysis. The algorithm is composed of three processes. First, a set of range images is captured from various viewpoints surrounding the object of interest. In addition, a set of multi-modal images is acquired. Then, a multi-resolution analysis based on the quincunx wavelet transform is performed. The multi- resolution analysis allows extraction of multi-resolution detail areas. These areas of details are projected back onto the surface of the initial model. Detail areas are marked onto the model and constitute another modality. Finally, a mesh simplification is performed to reduce data that are not marked as detail. This approach can be applied to any 3D models containing multi-modal information in order to allow fast rendering and manipulation. This method also allows 3D data de-noising.

  5. A 3D-Video-Based Computerized Analysis of Social and Sexual Interactions in Rats

    PubMed Central

    Matsumoto, Jumpei; Urakawa, Susumu; Takamura, Yusaku; Malcher-Lopes, Renato; Hori, Etsuro; Tomaz, Carlos; Ono, Taketoshi; Nishijo, Hisao

    2013-01-01

    A large number of studies have analyzed social and sexual interactions between rodents in relation to neural activity. Computerized video analysis has been successfully used to detect numerous behaviors quickly and objectively; however, to date only 2D video recording has been used, which cannot determine the 3D locations of animals and encounters difficulties in tracking animals when they are overlapping, e.g., when mounting. To overcome these limitations, we developed a novel 3D video analysis system for examining social and sexual interactions in rats. A 3D image was reconstructed by integrating images captured by multiple depth cameras at different viewpoints. The 3D positions of body parts of the rats were then estimated by fitting skeleton models of the rats to the 3D images using a physics-based fitting algorithm, and various behaviors were recognized based on the spatio-temporal patterns of the 3D movements of the body parts. Comparisons between the data collected by the 3D system and those by visual inspection indicated that this system could precisely estimate the 3D positions of body parts for 2 rats during social and sexual interactions with few manual interventions, and could compute the traces of the 2 animals even during mounting. We then analyzed the effects of AM-251 (a cannabinoid CB1 receptor antagonist) on male rat sexual behavior, and found that AM-251 decreased movements and trunk height before sexual behavior, but increased the duration of head-head contact during sexual behavior. These results demonstrate that the use of this 3D system in behavioral studies could open the door to new approaches for investigating the neuroscience of social and sexual behavior. PMID:24205238

  6. A 3D-video-based computerized analysis of social and sexual interactions in rats.

    PubMed

    Matsumoto, Jumpei; Urakawa, Susumu; Takamura, Yusaku; Malcher-Lopes, Renato; Hori, Etsuro; Tomaz, Carlos; Ono, Taketoshi; Nishijo, Hisao

    2013-01-01

    A large number of studies have analyzed social and sexual interactions between rodents in relation to neural activity. Computerized video analysis has been successfully used to detect numerous behaviors quickly and objectively; however, to date only 2D video recording has been used, which cannot determine the 3D locations of animals and encounters difficulties in tracking animals when they are overlapping, e.g., when mounting. To overcome these limitations, we developed a novel 3D video analysis system for examining social and sexual interactions in rats. A 3D image was reconstructed by integrating images captured by multiple depth cameras at different viewpoints. The 3D positions of body parts of the rats were then estimated by fitting skeleton models of the rats to the 3D images using a physics-based fitting algorithm, and various behaviors were recognized based on the spatio-temporal patterns of the 3D movements of the body parts. Comparisons between the data collected by the 3D system and those by visual inspection indicated that this system could precisely estimate the 3D positions of body parts for 2 rats during social and sexual interactions with few manual interventions, and could compute the traces of the 2 animals even during mounting. We then analyzed the effects of AM-251 (a cannabinoid CB1 receptor antagonist) on male rat sexual behavior, and found that AM-251 decreased movements and trunk height before sexual behavior, but increased the duration of head-head contact during sexual behavior. These results demonstrate that the use of this 3D system in behavioral studies could open the door to new approaches for investigating the neuroscience of social and sexual behavior.

  7. Mobile 3D quality of experience evaluation: a hybrid data collection and analysis approach

    NASA Astrophysics Data System (ADS)

    Utriainen, Timo; Häyrynen, Jyrki; Jumisko-Pyykkö, Satu; Boev, Atanas; Gotchev, Atanas; Hannuksela, Miska M.

    2011-02-01

    The paper presents a hybrid approach to study the user's experienced quality of 3D visual content on mobile autostereoscopic displays. It combines extensive subjective tests with collection and objective analysis of eye-tracked data. 3D cues which are significant for mobiles are simulated in the generated 3D test content. The methodology for conducting subjective quality evaluation includes hybrid data-collection of quantitative quality preferences, qualitative impressions, and binocular eye-tracking. We present early results of the subjective tests along with eye movement reaction times, areas of interest and heatmaps obtained from raw eye-tracked data after statistical analysis. The study contributes to the question what is important to be visualized on portable auto-stereoscopic displays and how to maintain and visually enhance the quality of 3D content for such displays.

  8. Online interactive analysis of protein structure ensembles with Bio3D-web.

    PubMed

    Skjærven, Lars; Jariwala, Shashank; Yao, Xin-Qiu; Grant, Barry J

    2016-11-15

    Bio3D-web is an online application for analyzing the sequence, structure and conformational heterogeneity of protein families. Major functionality is provided for identifying protein structure sets for analysis, their alignment and refined structure superposition, sequence and structure conservation analysis, mapping and clustering of conformations and the quantitative comparison of their predicted structural dynamics. Bio3D-web is based on the Bio3D and Shiny R packages. All major browsers are supported and full source code is available under a GPL2 license from http://thegrantlab.org/bio3d-web CONTACT: bjgrant@umich.edu or lars.skjarven@uib.no. © The Author 2016. Published by Oxford University Press.

  9. Human factors flight trial analysis for 3D SVS: part II

    NASA Astrophysics Data System (ADS)

    Schiefele, Jens; Howland, Duncan; Maris, John; Pschierer, Christian; Wipplinger, Patrick; Meuter, Michael

    2005-05-01

    This paper describes flight trials performed in Centennial, CO using a Piper Cheyenne owned and operated by Marinvent. The goal of the flight trial was to evaluate the objective performance of pilots using conventional paper charts or a 3D SVS display. Six pilots flew thirty-six approaches to the Colorado Springs airport to accomplish this goal. As dependent variables, positional accuracy and situational awareness probe (SAP) statistics were measured while analysis was conducted by an ANOVA test. In parallel, all pilots answered subjective Cooper-Harper, NASA TLX, situation awareness rating technique (SART), Display Readability Rating, Display Flyability Rating and debriefing questionnaires. Three different settings (paper chart, electronic navigation chart, 3D SVS display) were evaluated in a totally randomized manner. This paper describes the comparison between the conventional paper chart and the 3D SVS display. The 3D SVS primary flight display provides a depiction of primary flight data as well as a 3D depiction of airports, terrain and obstacles. In addition, a 3D dynamic channel visualizing the selected approach procedure can be displayed. The result shows that pilots flying the 3D SVS display perform no worse than pilots with the conventional paper chart. Flight technical error and workload are lower, situational awareness is equivalent with conventional paper charts.

  10. Lead-oriented synthesis: Investigation of organolithium-mediated routes to 3-D scaffolds and 3-D shape analysis of a virtual lead-like library.

    PubMed

    Lüthy, Monique; Wheldon, Mary C; Haji-Cheteh, Chehasnah; Atobe, Masakazu; Bond, Paul S; O'Brien, Peter; Hubbard, Roderick E; Fairlamb, Ian J S

    2015-06-01

    Synthetic routes to six 3-D scaffolds containing piperazine, pyrrolidine and piperidine cores have been developed. The synthetic methodology focused on the use of N-Boc α-lithiation-trapping chemistry. Notably, suitably protected and/or functionalised medicinal chemistry building blocks were synthesised via concise, connective methodology. This represents a rare example of lead-oriented synthesis. A virtual library of 190 compounds was then enumerated from the six scaffolds. Of these, 92 compounds (48%) fit the lead-like criteria of: (i) -1⩽AlogP⩽3; (ii) 14⩽number of heavy atoms⩽26; (iii) total polar surface area⩾50Å(2). The 3-D shapes of the 190 compounds were analysed using a triangular plot of normalised principal moments of inertia (PMI). From this, 46 compounds were identified which had lead-like properties and possessed 3-D shapes in under-represented areas of pharmaceutical space. Thus, the PMI analysis of the 190 member virtual library showed that whilst scaffolds which may appear on paper to be 3-D in shape, only 24% of the compounds actually had 3-D structures in the more interesting areas of 3-D drug space.

  11. Sensitivity Analysis of the Scattering-Based SARBM3D Despeckling Algorithm

    PubMed Central

    Di Simone, Alessio

    2016-01-01

    Synthetic Aperture Radar (SAR) imagery greatly suffers from multiplicative speckle noise, typical of coherent image acquisition sensors, such as SAR systems. Therefore, a proper and accurate despeckling preprocessing step is almost mandatory to aid the interpretation and processing of SAR data by human users and computer algorithms, respectively. Very recently, a scattering-oriented version of the popular SAR Block-Matching 3D (SARBM3D) despeckling filter, named Scattering-Based (SB)-SARBM3D, was proposed. The new filter is based on the a priori knowledge of the local topography of the scene. In this paper, an experimental sensitivity analysis of the above-mentioned despeckling algorithm is carried out, and the main results are shown and discussed. In particular, the role of both electromagnetic and geometrical parameters of the surface and the impact of its scattering behavior are investigated. Furthermore, a comprehensive sensitivity analysis of the SB-SARBM3D filter against the Digital Elevation Model (DEM) resolution and the SAR image-DEM coregistration step is also provided. The sensitivity analysis shows a significant robustness of the algorithm against most of the surface parameters, while the DEM resolution plays a key role in the despeckling process. Furthermore, the SB-SARBM3D algorithm outperforms the original SARBM3D in the presence of the most realistic scattering behaviors of the surface. An actual scenario is also presented to assess the DEM role in real-life conditions. PMID:27347971

  12. Sensitivity Analysis of the Scattering-Based SARBM3D Despeckling Algorithm.

    PubMed

    Di Simone, Alessio

    2016-06-25

    Synthetic Aperture Radar (SAR) imagery greatly suffers from multiplicative speckle noise, typical of coherent image acquisition sensors, such as SAR systems. Therefore, a proper and accurate despeckling preprocessing step is almost mandatory to aid the interpretation and processing of SAR data by human users and computer algorithms, respectively. Very recently, a scattering-oriented version of the popular SAR Block-Matching 3D (SARBM3D) despeckling filter, named Scattering-Based (SB)-SARBM3D, was proposed. The new filter is based on the a priori knowledge of the local topography of the scene. In this paper, an experimental sensitivity analysis of the above-mentioned despeckling algorithm is carried out, and the main results are shown and discussed. In particular, the role of both electromagnetic and geometrical parameters of the surface and the impact of its scattering behavior are investigated. Furthermore, a comprehensive sensitivity analysis of the SB-SARBM3D filter against the Digital Elevation Model (DEM) resolution and the SAR image-DEM coregistration step is also provided. The sensitivity analysis shows a significant robustness of the algorithm against most of the surface parameters, while the DEM resolution plays a key role in the despeckling process. Furthermore, the SB-SARBM3D algorithm outperforms the original SARBM3D in the presence of the most realistic scattering behaviors of the surface. An actual scenario is also presented to assess the DEM role in real-life conditions.

  13. 3D texture analysis in renal cell carcinoma tissue image grading.

    PubMed

    Kim, Tae-Yun; Cho, Nam-Hoon; Jeong, Goo-Bo; Bengtsson, Ewert; Choi, Heung-Kook

    2014-01-01

    One of the most significant processes in cancer cell and tissue image analysis is the efficient extraction of features for grading purposes. This research applied two types of three-dimensional texture analysis methods to the extraction of feature values from renal cell carcinoma tissue images, and then evaluated the validity of the methods statistically through grade classification. First, we used a confocal laser scanning microscope to obtain image slices of four grades of renal cell carcinoma, which were then reconstructed into 3D volumes. Next, we extracted quantitative values using a 3D gray level cooccurrence matrix (GLCM) and a 3D wavelet based on two types of basis functions. To evaluate their validity, we predefined 6 different statistical classifiers and applied these to the extracted feature sets. In the grade classification results, 3D Haar wavelet texture features combined with principal component analysis showed the best discrimination results. Classification using 3D wavelet texture features was significantly better than 3D GLCM, suggesting that the former has potential for use in a computer-based grading system.

  14. 3D Texture Analysis in Renal Cell Carcinoma Tissue Image Grading

    PubMed Central

    Cho, Nam-Hoon; Choi, Heung-Kook

    2014-01-01

    One of the most significant processes in cancer cell and tissue image analysis is the efficient extraction of features for grading purposes. This research applied two types of three-dimensional texture analysis methods to the extraction of feature values from renal cell carcinoma tissue images, and then evaluated the validity of the methods statistically through grade classification. First, we used a confocal laser scanning microscope to obtain image slices of four grades of renal cell carcinoma, which were then reconstructed into 3D volumes. Next, we extracted quantitative values using a 3D gray level cooccurrence matrix (GLCM) and a 3D wavelet based on two types of basis functions. To evaluate their validity, we predefined 6 different statistical classifiers and applied these to the extracted feature sets. In the grade classification results, 3D Haar wavelet texture features combined with principal component analysis showed the best discrimination results. Classification using 3D wavelet texture features was significantly better than 3D GLCM, suggesting that the former has potential for use in a computer-based grading system. PMID:25371701

  15. 3D video analysis of the novel object recognition test in rats.

    PubMed

    Matsumoto, Jumpei; Uehara, Takashi; Urakawa, Susumu; Takamura, Yusaku; Sumiyoshi, Tomiki; Suzuki, Michio; Ono, Taketoshi; Nishijo, Hisao

    2014-10-01

    The novel object recognition (NOR) test has been widely used to test memory function. We developed a 3D computerized video analysis system that estimates nose contact with an object in Long Evans rats to analyze object exploration during NOR tests. The results indicate that the 3D system reproducibly and accurately scores the NOR test. Furthermore, the 3D system captures a 3D trajectory of the nose during object exploration, enabling detailed analyses of spatiotemporal patterns of object exploration. The 3D trajectory analysis revealed a specific pattern of object exploration in the sample phase of the NOR test: normal rats first explored the lower parts of objects and then gradually explored the upper parts. A systematic injection of MK-801 suppressed changes in these exploration patterns. The results, along with those of previous studies, suggest that the changes in the exploration patterns reflect neophobia to a novel object and/or changes from spatial learning to object learning. These results demonstrate that the 3D tracking system is useful not only for detailed scoring of animal behaviors but also for investigation of characteristic spatiotemporal patterns of object exploration. The system has the potential to facilitate future investigation of neural mechanisms underlying object exploration that result from dynamic and complex brain activity.

  16. Development of multiple QSAR models for consensus predictions and unified mechanistic interpretations of the free-radical scavenging activities of chromone derivatives.

    PubMed

    Mitra, Indrani; Saha, Achintya; Roy, Kunal

    2012-05-01

    Antioxidants are important defenders of the human body against nocive free radicals, which are the causative agents of most life-threatening diseases. The immense biomedicinal utility of antioxidants necessitates the development and design of new synthetic antioxidant molecules. The present report deals with the modeling of a series of chromone derivatives, which was done to provide detailed insight into the main structural fragments that impart antioxidant activity to these molecules. Four different quantitative structure-property relationship (QSAR) techniques, namely 3D pharmacophore mapping, comparative molecular similarity indices analysis (CoMSIA 3D-QSAR), hologram QSAR (HQSAR), and group-based QSAR (G-QSAR) techniques, were employed to obtain statistically significant models with encouraging external predictive potentials. Moreover, the visual contribution maps obtained for the different models signify the importance of different structural features in specific regions of the chromone nucleus. Additionally, the G-QSAR models determine the composite influence of pairs of substituent fragments on the overall antioxidant activity profiles of the molecules. Multiple models with different strategies for assessing structure-activity relationships were applied to reach a unified conclusion regarding the antioxidant mechanism and to provide consensus predictions, which are more reliable than values derived from a single model. The structural information obtained from the various QSAR models developed in the present work can thus be effectively utilized to design and predict the activities of new molecules belonging to the class of chromone derivatives.

  17. Advances in Genomic Profiling and Analysis of 3D Chromatin Structure and Interaction.

    PubMed

    Tang, Binhua; Cheng, Xiaolong; Xi, Yunlong; Chen, Zixin; Zhou, Yufan; Jin, Victor X

    2017-09-08

    Recent sequence-based profiling technologies such as high-throughput sequencing to detect fragment nucleotide sequence (Hi-C) and chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) have revolutionized the field of three-dimensional (3D) chromatin architecture. It is now recognized that human genome functions as folded 3D chromatin units and looping paradigm is the basic principle of gene regulation. To better interpret the 3D data dramatically accumulating in past five years and to gain deep biological insights, huge efforts have been made in developing novel quantitative analysis methods. However, the full understanding of genome regulation requires thorough knowledge in both genomic technologies and their related data analyses. We summarize the recent advances in genomic technologies in identifying the 3D chromatin structure and interaction, and illustrate the quantitative analysis methods to infer functional domains and chromatin interactions, and further elucidate the emerging single-cell Hi-C technique and its computational analysis, and finally discuss the future directions such as advances of 3D chromatin techniques in diseases.

  18. Fully-coupled analysis of jet mixing problems. Three-dimensional PNS model, SCIP3D

    NASA Technical Reports Server (NTRS)

    Wolf, D. E.; Sinha, N.; Dash, S. M.

    1988-01-01

    Numerical procedures formulated for the analysis of 3D jet mixing problems, as incorporated in the computer model, SCIP3D, are described. The overall methodology closely parallels that developed in the earlier 2D axisymmetric jet mixing model, SCIPVIS. SCIP3D integrates the 3D parabolized Navier-Stokes (PNS) jet mixing equations, cast in mapped cartesian or cylindrical coordinates, employing the explicit MacCormack Algorithm. A pressure split variant of this algorithm is employed in subsonic regions with a sublayer approximation utilized for treating the streamwise pressure component. SCIP3D contains both the ks and kW turbulence models, and employs a two component mixture approach to treat jet exhausts of arbitrary composition. Specialized grid procedures are used to adjust the grid growth in accordance with the growth of the jet, including a hybrid cartesian/cylindrical grid procedure for rectangular jets which moves the hybrid coordinate origin towards the flow origin as the jet transitions from a rectangular to circular shape. Numerous calculations are presented for rectangular mixing problems, as well as for a variety of basic unit problems exhibiting overall capabilities of SCIP3D.

  19. Model-based 3-D scene analysis from stereoscopic image sequences

    NASA Astrophysics Data System (ADS)

    Koch, Reinhard

    A vision-based 3-D scene analysis system is described that is capable to model complex real-world scences like buildings automatically from stereoscopic image pairs. Input to the system is a sequence of stereoscopic images taken with two standard CCD Cameras and TV lenses. The relative orientation of both cameras to each other is known by calibration. The camera pair is then moved throughout the scene and a long sequence of closely spaced views is recorded. Each of the stereoscopic image pairs is rectified and a dense map of 3-D surface points is obtained by area correlation, object segmentation, interpolation, and triangulation. 3-D camera motion relative to the scene coordinate system is tracked directly from the image sequence which allows to fuse 3-D surface measurements from different view points into a consistent 3-D model scence. The surface geometry of each scene object is approximated by a triangular surface mesh which stores the surface texture in a texture map. From the textured 3-D models, realistic looking image sequences from arbitrary view points can be synthesized using computer graphics.

  20. Quantitative comparison of 3D and 2.5D gamma analysis: introducing gamma angle histograms

    NASA Astrophysics Data System (ADS)

    Sa'd, M. Al; Graham, J.; Liney, G. P.; Moore, C. J.

    2013-04-01

    Comparison of dose distributions using the 3D gamma method is anticipated to provide better indicators for the quality assurance process than the 2.5D (stacked 2D slice-by-slice) gamma calculation, especially for advanced radiotherapy technologies. This study compares the accuracy of the 3D and 2.5D gamma calculation methods. 3D and 2.5D gamma calculations were carried out on four reference/evaluation 3D dose sample pairs. A number of analysis methods were used, including average gamma and gamma volume histograms. We introduce the concept of gamma-angle histograms. Noise sensitivity tests were also performed using two different noise models. The advantage of the 3D gamma method showed up as a higher proportion of points passing the tolerance criteria of 3% dose difference and 3 mm distance-to-agreement (DTA), with considerably lower average gamma values, a lower influence of the DTA criterion, and a higher noise tolerance. The 3D gamma approach is more reliable than the 2.5D approach in terms of providing comprehensive quantitative results, which are needed in quality assurance procedures for advanced radiotherapy methods.

  1. Analysis of scalability of high-performance 3D image processing platform for virtual colonoscopy.

    PubMed

    Yoshida, Hiroyuki; Wu, Yin; Cai, Wenli

    2014-03-19

    One of the key challenges in three-dimensional (3D) medical imaging is to enable the fast turn-around time, which is often required for interactive or real-time response. This inevitably requires not only high computational power but also high memory bandwidth due to the massive amount of data that need to be processed. For this purpose, we previously developed a software platform for high-performance 3D medical image processing, called HPC 3D-MIP platform, which employs increasingly available and affordable commodity computing systems such as the multicore, cluster, and cloud computing systems. To achieve scalable high-performance computing, the platform employed size-adaptive, distributable block volumes as a core data structure for efficient parallelization of a wide range of 3D-MIP algorithms, supported task scheduling for efficient load distribution and balancing, and consisted of a layered parallel software libraries that allow image processing applications to share the common functionalities. We evaluated the performance of the HPC 3D-MIP platform by applying it to computationally intensive processes in virtual colonoscopy. Experimental results showed a 12-fold performance improvement on a workstation with 12-core CPUs over the original sequential implementation of the processes, indicating the efficiency of the platform. Analysis of performance scalability based on the Amdahl's law for symmetric multicore chips showed the potential of a high performance scalability of the HPC 3D-MIP platform when a larger number of cores is available.

  2. Analysis of scalability of high-performance 3D image processing platform for virtual colonoscopy

    PubMed Central

    Yoshida, Hiroyuki; Wu, Yin; Cai, Wenli

    2014-01-01

    One of the key challenges in three-dimensional (3D) medical imaging is to enable the fast turn-around time, which is often required for interactive or real-time response. This inevitably requires not only high computational power but also high memory bandwidth due to the massive amount of data that need to be processed. For this purpose, we previously developed a software platform for high-performance 3D medical image processing, called HPC 3D-MIP platform, which employs increasingly available and affordable commodity computing systems such as the multicore, cluster, and cloud computing systems. To achieve scalable high-performance computing, the platform employed size-adaptive, distributable block volumes as a core data structure for efficient parallelization of a wide range of 3D-MIP algorithms, supported task scheduling for efficient load distribution and balancing, and consisted of a layered parallel software libraries that allow image processing applications to share the common functionalities. We evaluated the performance of the HPC 3D-MIP platform by applying it to computationally intensive processes in virtual colonoscopy. Experimental results showed a 12-fold performance improvement on a workstation with 12-core CPUs over the original sequential implementation of the processes, indicating the efficiency of the platform. Analysis of performance scalability based on the Amdahl’s law for symmetric multicore chips showed the potential of a high performance scalability of the HPC 3D-MIP platform when a larger number of cores is available. PMID:24910506

  3. 3D finite element analysis of porous Ti-based alloy prostheses.

    PubMed

    Mircheski, Ile; Gradišar, Marko

    2016-11-01

    In this paper, novel designs of porous acetabular cups are created and tested with 3D finite element analysis (FEA). The aim is to develop a porous acetabular cup with low effective radial stiffness of the structure, which will be near to the architectural and mechanical behavior of the natural bone. For the realization of this research, a 3D-scanner technology was used for obtaining a 3D-CAD model of the pelvis bone, a 3D-CAD software for creating a porous acetabular cup, and a 3D-FEA software for virtual testing of a novel design of the porous acetabular cup. The results obtained from this research reveal that a porous acetabular cup from Ti-based alloys with 60 ± 5% porosity has the mechanical behavior and effective radial stiffness (Young's modulus in radial direction) that meet and exceed the required properties of the natural bone. The virtual testing with 3D-FEA of a novel design with porous structure during the very early stage of the design and the development of orthopedic implants, enables obtaining a new or improved biomedical implant for a relatively short time and reduced price.

  4. Non-invasive volumetric analysis of asymptomatic hands using a 3-D scanner

    PubMed Central

    Shinkai, Hiroki; Yamamoto, Michiro; Tatebe, Masahiro; Iwatsuki, Katsuyuki; Kurimoto, Shigeru; Hirata, Hitoshi

    2017-01-01

    Hand swelling is one of the symptoms often seen in practice, but none of the available morphometric methods can quickly and efficiently quantify hand volume in an objective manner, and the current gold-standard volume measurement requires immersion in water, which can be difficult to use. Therefore, we aimed to analyze the accuracy of using 3-dimensional (3-D) scanning to measure hand volume. First, we compared the hand volume calculated using the 3-D scanner to that calculated from the conventional method among 109 volunteers to determine the reliability of 3-D measurements. We defined the beginning of the hand as the distal wrist crease, and 3-D forms of the hands were captured by the 3-D scanning system. Second, 238 volunteers (87 men, 151 women) with no disease or history of hand surgery underwent 3-D scanning. Data collected included age, height, weight, and shoe size. The wrist circumference (WC) and the distance between distal wrist crease and tip of middle finger (DDT) were measured. Statistical analyses were performed using linear regression to investigate the relationship between the hand volume and these parameters. In the first study, a significantly strong positive correlation was observed [R = 0.98] between the hand volume calculated via 3-D scanning and that calculated via the conventional method. In the second study, no significant differences between the volumes, WC or DDT of right and left hands were found. The correlations of hand volume with weight, WC, and DDT were strong. We created a formula to predict the hand volume using these parameters; these variables explained approximately 80% of the predicted volume. We confirmed that the new 3-D scanning method, which is performed without touching the hand and can record the form of the hand, yields an accurate volumetric analysis of an asymptomatic hand. PMID:28796816

  5. Method of Individual Adjustment for 3D CT Analysis: Linear Measurement

    PubMed Central

    Choi, Dong Hun; Lee, Jeong Woo; Yang, Jung Dug; Chung, Ho Yun; Cho, Byung Chae

    2016-01-01

    Introduction. We aim to regularize measurement values in three-dimensional (3D) computed tomography (CT) reconstructed images for higher-precision 3D analysis, focusing on length-based 3D cephalometric examinations. Methods. We measure the linear distances between points on different skull models using Vernier calipers (real values). We use 10 differently tilted CT scans for 3D CT reconstruction of the models and measure the same linear distances from the picture archiving and communication system (PACS). In both cases, each measurement is performed three times by three doctors, yielding nine measurements. The real values are compared with the PACS values. Each PACS measurement is revised based on the display field of view (DFOV) values and compared with the real values. Results. The real values and the PACS measurement changes according to tilt value have no significant correlations (p > 0.05). However, significant correlations appear between the real values and DFOV-adjusted PACS measurements (p < 0.001). Hence, we obtain a correlation expression that can yield real physical values from PACS measurements. The DFOV value intervals for various age groups are also verified. Conclusion. Precise confirmation of individual preoperative length and precise analysis of postoperative improvements through 3D analysis is possible, which is helpful for facial-bone-surgery symmetry correction. PMID:28070517

  6. Method of Individual Adjustment for 3D CT Analysis: Linear Measurement.

    PubMed

    Kim, Dong Kyu; Choi, Dong Hun; Lee, Jeong Woo; Yang, Jung Dug; Chung, Ho Yun; Cho, Byung Chae; Choi, Kang Young

    2016-01-01

    Introduction. We aim to regularize measurement values in three-dimensional (3D) computed tomography (CT) reconstructed images for higher-precision 3D analysis, focusing on length-based 3D cephalometric examinations. Methods. We measure the linear distances between points on different skull models using Vernier calipers (real values). We use 10 differently tilted CT scans for 3D CT reconstruction of the models and measure the same linear distances from the picture archiving and communication system (PACS). In both cases, each measurement is performed three times by three doctors, yielding nine measurements. The real values are compared with the PACS values. Each PACS measurement is revised based on the display field of view (DFOV) values and compared with the real values. Results. The real values and the PACS measurement changes according to tilt value have no significant correlations (p > 0.05). However, significant correlations appear between the real values and DFOV-adjusted PACS measurements (p < 0.001). Hence, we obtain a correlation expression that can yield real physical values from PACS measurements. The DFOV value intervals for various age groups are also verified. Conclusion. Precise confirmation of individual preoperative length and precise analysis of postoperative improvements through 3D analysis is possible, which is helpful for facial-bone-surgery symmetry correction.

  7. Visualization and analysis of 3D gene expression patterns in zebrafish using web services

    NASA Astrophysics Data System (ADS)

    Potikanond, D.; Verbeek, F. J.

    2012-01-01

    The analysis of patterns of gene expression patterns analysis plays an important role in developmental biology and molecular genetics. Visualizing both quantitative and spatio-temporal aspects of gene expression patterns together with referenced anatomical structures of a model-organism in 3D can help identifying how a group of genes are expressed at a certain location at a particular developmental stage of an organism. In this paper, we present an approach to provide an online visualization of gene expression data in zebrafish (Danio rerio) within 3D reconstruction model of zebrafish in different developmental stages. We developed web services that provide programmable access to the 3D reconstruction data and spatial-temporal gene expression data maintained in our local repositories. To demonstrate this work, we develop a web application that uses these web services to retrieve data from our local information systems. The web application also retrieve relevant analysis of microarray gene expression data from an external community resource; i.e. the ArrayExpress Atlas. All the relevant gene expression patterns data are subsequently integrated with the reconstruction data of the zebrafish atlas using ontology based mapping. The resulting visualization provides quantitative and spatial information on patterns of gene expression in a 3D graphical representation of the zebrafish atlas in a certain developmental stage. To deliver the visualization to the user, we developed a Java based 3D viewer client that can be integrated in a web interface allowing the user to visualize the integrated information over the Internet.

  8. Heat analysis of thermal overload relays using 3-D finite element method

    SciTech Connect

    Kawase, Yoshihiro; Ichihashi, Takayuki . Dept. of Information Science); Ito, Shokichi . Dept. of Electronics)

    1999-05-01

    In designing a thermal overload relay, it is necessary to analyze thermal characteristics of several trial models. Up to now, this has been done by measuring the temperatures on a number of positions in the trial models. This experimental method is undoubtedly expensive. In this paper, the temperature distribution of a thermal overload relay is obtained by using 3-D finite element analysis taking into account the current distribution in current-carrying conductors. It is shown that the 3-D analysis is capable of evaluating a new design of thermal overload relays.

  9. Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data

    NASA Astrophysics Data System (ADS)

    Strait, E. J.; King, J. D.; Hanson, J. M.; Logan, N. C.

    2016-11-01

    An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ˜10-3 to 10-5 of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

  10. Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data.

    PubMed

    Strait, E J; King, J D; Hanson, J M; Logan, N C

    2016-11-01

    An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ∼10(-3) to 10(-5) of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

  11. Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data

    SciTech Connect

    Strait, E. J.; King, J. D.; Hanson, J. M.; Logan, N. C.

    2016-08-11

    An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ~10-3 to 10-5 of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Lastly, applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

  12. Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data

    SciTech Connect

    Strait, E. J.; King, J. D.; Hanson, J. M.; Logan, N. C.

    2016-08-11

    An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ~10-3 to 10-5 of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Lastly, applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

  13. Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data

    DOE PAGES

    Strait, E. J.; King, J. D.; Hanson, J. M.; ...

    2016-08-11

    An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ~10-3 to 10-5 of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Lastly, applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

  14. 3D shape measurement of shoeprint impression with structured illumination and fringe pattern analysis

    NASA Astrophysics Data System (ADS)

    Su, Xianyu; Cao, Yiping; Xiang, Liqun; Chen, Wenjing

    2002-06-01

    The shoeprint impressions of suspect left at the crime scene can sometimes tell investigators what type of shoes to be looked for. These shoeprint impressions as one of the important evidence are useful in the detection of criminals. In this paper we propose a novel technique for identifying and analyzing the 3D characteristics of shoeprint impressions. We also design 3D shoeprint impression analysis system based on the combination the 3D shape measurement with structured illumination and fringe pattern analysis. We give a detail discussion on the principle and configuration of the system. Laboratory experiments show the technique is efficient in the detection of shoeprint and in the offering the reference for judicial evidence.

  15. 3D optical coherence tomography super pixel with machine classifier analysis for glaucoma detection.

    PubMed

    Xu, Juan; Ishikawa, Hiroshi; Wollstein, Gadi; Schuman, Joel S

    2011-01-01

    Current standard quantitative 3D spectral-domain optical coherence tomography (SD-OCT) analyses of various ocular diseases is limited in detecting structural damage at early pathologic stages. This is mostly because only a small fraction of the 3D data is used in the current method of quantifying the structure of interest. This paper presents a novel SD-OCT data analysis technique, taking full advantage of the 3D dataset. The proposed algorithm uses machine classifier to analyze SD-OCT images after grouping adjacent pixels into super pixel in order to detect glaucomatous damage. A 3D SD-OCT image is first converted into a 2D feature map and partitioned into over a hundred super pixels. Machine classifier analysis using boosting algorithm is performed on super pixel features. One hundred and ninety-two 3D OCT images of the optic nerve head region were tested. Area under the receiver operating characteristic (AUC) was computed to evaluate the glaucoma discrimination performance of the algorithm and compare it to the commercial software output. The AUC of normal vs glaucoma suspect eyes using the proposed method was statistically significantly higher than the current method (0.855 and 0.707, respectively, p=0.031). This new method has the potential to improve early detection of glaucomatous structural damages.

  16. Analysis of 3-D images of dental imprints using computer vision

    NASA Astrophysics Data System (ADS)

    Aubin, Michele; Cote, Jean; Laurendeau, Denis; Poussart, Denis

    1992-05-01

    This paper addressed two important aspects of dental analysis: (1) location and (2) identification of the types of teeth by means of 3-D image acquisition and segmentation. The 3-D images of both maxillaries are acquired using a wax wafer as support. The interstices between teeth are detected by non-linear filtering of the 3-D and grey-level data. Two operators are presented: one for the detection of the interstices between incisors, canines, and premolars and one for those between molars. Teeth are then identified by mapping the imprint under analysis on the computer model of an 'ideal' imprint. For the mapping to be valid, a set of three reference points is detected on the imprint. Then, the points are put in correspondence with similar points on the model. Two such points are chosen based on a least-squares fit of a second-order polynomial of the 3-D data in the area of canines. This area is of particular interest since the canines show a very characteristic shape and are easily detected on the imprint. The mapping technique is described in detail in the paper as well as pre-processing of the 3-D profiles. Experimental results are presented for different imprints.

  17. 3D texture analysis for classification of second harmonic generation images of human ovarian cancer

    NASA Astrophysics Data System (ADS)

    Wen, Bruce; Campbell, Kirby R.; Tilbury, Karissa; Nadiarnykh, Oleg; Brewer, Molly A.; Patankar, Manish; Singh, Vikas; Eliceiri, Kevin. W.; Campagnola, Paul J.

    2016-10-01

    Remodeling of the collagen architecture in the extracellular matrix (ECM) has been implicated in ovarian cancer. To quantify these alterations we implemented a form of 3D texture analysis to delineate the fibrillar morphology observed in 3D Second Harmonic Generation (SHG) microscopy image data of normal (1) and high risk (2) ovarian stroma, benign ovarian tumors (3), low grade (4) and high grade (5) serous tumors, and endometrioid tumors (6). We developed a tailored set of 3D filters which extract textural features in the 3D image sets to build (or learn) statistical models of each tissue class. By applying k-nearest neighbor classification using these learned models, we achieved 83–91% accuracies for the six classes. The 3D method outperformed the analogous 2D classification on the same tissues, where we suggest this is due the increased information content. This classification based on ECM structural changes will complement conventional classification based on genetic profiles and can serve as an additional biomarker. Moreover, the texture analysis algorithm is quite general, as it does not rely on single morphological metrics such as fiber alignment, length, and width but their combined convolution with a customizable basis set.

  18. 3D texture analysis for classification of second harmonic generation images of human ovarian cancer

    PubMed Central

    Wen, Bruce; Campbell, Kirby R.; Tilbury, Karissa; Nadiarnykh, Oleg; Brewer, Molly A.; Patankar, Manish; Singh, Vikas; Eliceiri, Kevin. W.; Campagnola, Paul J.

    2016-01-01

    Remodeling of the collagen architecture in the extracellular matrix (ECM) has been implicated in ovarian cancer. To quantify these alterations we implemented a form of 3D texture analysis to delineate the fibrillar morphology observed in 3D Second Harmonic Generation (SHG) microscopy image data of normal (1) and high risk (2) ovarian stroma, benign ovarian tumors (3), low grade (4) and high grade (5) serous tumors, and endometrioid tumors (6). We developed a tailored set of 3D filters which extract textural features in the 3D image sets to build (or learn) statistical models of each tissue class. By applying k-nearest neighbor classification using these learned models, we achieved 83–91% accuracies for the six classes. The 3D method outperformed the analogous 2D classification on the same tissues, where we suggest this is due the increased information content. This classification based on ECM structural changes will complement conventional classification based on genetic profiles and can serve as an additional biomarker. Moreover, the texture analysis algorithm is quite general, as it does not rely on single morphological metrics such as fiber alignment, length, and width but their combined convolution with a customizable basis set. PMID:27767180

  19. Clinical feasibility and validation of 3D principal strain analysis from cine MRI: comparison to 2D strain by MRI and 3D speckle tracking echocardiography.

    PubMed

    Satriano, Alessandro; Heydari, Bobak; Narous, Mariam; Exner, Derek V; Mikami, Yoko; Attwood, Monica M; Tyberg, John V; Lydell, Carmen P; Howarth, Andrew G; Fine, Nowell M; White, James A

    2017-07-06

    Two-dimensional (2D) strain analysis is constrained by geometry-dependent reference directions of deformation (i.e. radial, circumferential, and longitudinal) following the assumption of cylindrical chamber architecture. Three-dimensional (3D) principal strain analysis may overcome such limitations by referencing intrinsic (i.e. principal) directions of deformation. This study aimed to demonstrate clinical feasibility of 3D principal strain analysis from routine 2D cine MRI with validation to strain from 2D tagged cine analysis and 3D speckle tracking echocardiography. Thirty-one patients undergoing cardiac MRI were studied. 3D strain was measured from routine, multi-planar 2D cine SSFP images using custom software designed to apply 4D deformation fields to 3D cardiac models to derive principal strain. Comparisons of strain estimates versus those by 2D tagged cine, 2D non-tagged cine (feature tracking), and 3D speckle tracking echocardiography (STE) were performed. Mean age was 51 ± 14 (36% female). Mean LV ejection fraction was 66 ± 10% (range 37-80%). 3D principal strain analysis was feasible in all subjects and showed high inter- and intra-observer reproducibility (ICC range 0.83-0.97 and 0.83-0.98, respectively-p < 0.001 for all directions). Strong correlations of minimum and maximum principal strain were respectively observed versus the following: 3D STE estimates of longitudinal (r = 0.81 and r = -0.64), circumferential (r = 0.76 and r = -0.58) and radial (r = -0.80 and r = 0.63) strain (p < 0.001 for all); 2D tagged cine estimates of longitudinal (r = 0.81 and r = -0.81), circumferential (r = 0.87 and r = -0.85), and radial (r = -0.76 and r = 0.81) strain (p < 0.0001 for all); and 2D cine (feature tracking) estimates of longitudinal (r = 0.85 and -0.83), circumferential (r = 0.88 and r = -0.87), and radial strain (r = -0.79 and r = 0.84, p < 0.0001 for all). 3D

  20. 3-D QSAR ANALYSIS OF INHIBITION OF MURINE SOLUBLE EPOXIDE HYDROLASE (MSEH) BY BENZOYLUREAS, ARYLUREAS, AND THEIR ANALOGUES. (R825433)

    EPA Science Inventory

    Two hundred and seventy-one compounds including benzoylureas, arylureas and related compounds were assayed using recombinant murine soluble epoxide hydrolase (MsEH) produced from a baculovirus expression system. Among all the insect growth regulators assayed, 18 benzoylphenylu...

  1. 3-D QSAR ANALYSIS OF INHIBITION OF MURINE SOLUBLE EPOXIDE HYDROLASE (MSEH) BY BENZOYLUREAS, ARYLUREAS, AND THEIR ANALOGUES. (R825433)

    EPA Science Inventory

    Two hundred and seventy-one compounds including benzoylureas, arylureas and related compounds were assayed using recombinant murine soluble epoxide hydrolase (MsEH) produced from a baculovirus expression system. Among all the insect growth regulators assayed, 18 benzoylphenylu...

  2. Application of multi-resolution 3D techniques in crime scene documentation with bloodstain pattern analysis.

    PubMed

    Hołowko, Elwira; Januszkiewicz, Kamil; Bolewicki, Paweł; Sitnik, Robert; Michoński, Jakub

    2016-10-01

    In forensic documentation with bloodstain pattern analysis (BPA) it is highly desirable to obtain non-invasively overall documentation of a crime scene, but also register in high resolution single evidence objects, like bloodstains. In this study, we propose a hierarchical 3D scanning platform designed according to the top-down approach known from the traditional forensic photography. The overall 3D model of a scene is obtained via integration of laser scans registered from different positions. Some parts of a scene being particularly interesting are documented using midrange scanner, and the smallest details are added in the highest resolution as close-up scans. The scanning devices are controlled using developed software equipped with advanced algorithms for point cloud processing. To verify the feasibility and effectiveness of multi-resolution 3D scanning in crime scene documentation, our platform was applied to document a murder scene simulated by the BPA experts from the Central Forensic Laboratory of the Police R&D, Warsaw, Poland. Applying the 3D scanning platform proved beneficial in the documentation of a crime scene combined with BPA. The multi-resolution 3D model enables virtual exploration of a scene in a three-dimensional environment, distance measurement, and gives a more realistic preservation of the evidences together with their surroundings. Moreover, high-resolution close-up scans aligned in a 3D model can be used to analyze bloodstains revealed at the crime scene. The result of BPA such as trajectories, and the area of origin are visualized and analyzed in an accurate model of a scene. At this stage, a simplified approach considering the trajectory of blood drop as a straight line is applied. Although the 3D scanning platform offers a new quality of crime scene documentation with BPA, some of the limitations of the technique are also mentioned.

  3. Multi-Layer Identification of Highly-Potent ABCA1 Up-Regulators Targeting LXRβ Using Multiple QSAR Modeling, Structural Similarity Analysis, and Molecular Docking.

    PubMed

    Chen, Meimei; Yang, Fafu; Kang, Jie; Yang, Xuemei; Lai, Xinmei; Gao, Yuxing

    2016-11-29

    In this study, in silico approaches, including multiple QSAR modeling, structural similarity analysis, and molecular docking, were applied to develop QSAR classification models as a fast screening tool for identifying highly-potent ABCA1 up-regulators targeting LXRβ based on a series of new flavonoids. Initially, four modeling approaches, including linear discriminant analysis, support vector machine, radial basis function neural network, and classification and regression trees, were applied to construct different QSAR classification models. The statistics results indicated that these four kinds of QSAR models were powerful tools for screening highly potent ABCA1 up-regulators. Then, a consensus QSAR model was developed by combining the predictions from these four models. To discover new ABCA1 up-regulators at maximum accuracy, the compounds in the ZINC database that fulfilled the requirement of structural similarity of 0.7 compared to known potent ABCA1 up-regulator were subjected to the consensus QSAR model, which led to the discovery of 50 compounds. Finally, they were docked into the LXRβ binding site to understand their role in up-regulating ABCA1 expression. The excellent binding modes and docking scores of 10 hit compounds suggested they were highly-potent ABCA1 up-regulators targeting LXRβ. Overall, this study provided an effective strategy to discover highly potent ABCA1 up-regulators.

  4. Comparison of 3D quantitative structure-activity relationship methods: Analysis of the in vitro antimalarial activity of 154 artemisinin analogues by hypothetical active-site lattice and comparative molecular field analysis

    NASA Astrophysics Data System (ADS)

    Woolfrey, John R.; Avery, Mitchell A.; Doweyko, Arthur M.

    1998-03-01

    Two three-dimensional quantitative structure-activity relationship (3D-QSAR) methods, comparative molecular field analysis (CoMFA) and hypothetical active site lattice (HASL), were compared with respect to the analysis of a training set of 154 artemisinin analogues. Five models were created, including a complete HASL and two trimmed versions, as well as two CoMFA models (leave-one-out standard CoMFA and the guided-region selection protocol). Similar r2 and q2 values were obtained by each method, although some striking differences existed between CoMFA contour maps and the HASL output. Each of the four predictive models exhibited a similar ability to predict the activity of a test set of 23 artemisinin analogues, although some differences were noted as to which compounds were described well by either model.

  5. Application of FUN3D and CFL3D to the Third Workshop on CFD Uncertainty Analysis

    NASA Technical Reports Server (NTRS)

    Rumsey, C. L.; Thomas, J. L.

    2008-01-01

    Two Reynolds-averaged Navier-Stokes computer codes - one unstructured and one structured - are applied to two workshop cases (for the 3rd Workshop on CFD Uncertainty Analysis, held at Instituto Superior Tecnico, Lisbon, in October 2008) for the purpose of uncertainty analysis. The Spalart-Allmaras turbulence model is employed. The first case uses the method of manufactured solution and is intended as a verification case. In other words, the CFD solution is expected to approach the exact solution as the grid is refined. The second case is a validation case (comparison against experiment), for which modeling errors inherent in the turbulence model and errors/uncertainty in the experiment may prevent close agreement. The results from the two computer codes are also compared. This exercise verifies that the codes are consistent both with the exact manufactured solution and with each other. In terms of order property, both codes behave as expected for the manufactured solution. For the backward facing step, CFD uncertainty on the finest grid is computed and is generally very low for both codes (whose results are nearly identical). Agreement with experiment is good at some locations for particular variables, but there are also many areas where the CFD and experimental uncertainties do not overlap.

  6. Discovery of new potent human protein tyrosine phosphatase inhibitors via pharmacophore and QSAR analysis followed by in silico screening.

    PubMed

    Taha, Mutasem O; Bustanji, Yasser; Al-Bakri, Amal G; Yousef, Al-Motassem; Zalloum, Waleed A; Al-Masri, Ihab M; Atallah, Naji

    2007-03-01

    A pharmacophoric model was developed for human protein tyrosine phosphatase 1B (h-PTP 1B) inhibitors utilizing the HipHop-REFINE module of CATALYST software. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of physicochemical descriptors and pharmacophore hypothesis that yield consistent QSAR equation of good predictive potential (r = 0.87,F-statistic = 69.13,r(BS)2 = 0.76,r(LOO)2 = 0.68). The validity of the QSAR equation and the associated pharmacophoric hypothesis was experimentally established by the identification of five new h-PTP 1B inhibitors retrieved from the National Cancer Institute (NCI) database.

  7. Statistical analysis of cell migration in 3D using the anisotropic persistent random walk model.

    PubMed

    Wu, Pei-Hsun; Giri, Anjil; Wirtz, Denis

    2015-03-01

    Cell migration through 3D extracellular matrices (ECMs) is crucial to the normal development of tissues and organs and in disease processes, yet adequate analytical tools to characterize 3D migration are lacking. The motility of eukaryotic cells on 2D substrates in the absence of gradients has long been described using persistent random walks (PRWs). Recent work shows that 3D migration is anisotropic and features an exponential mean cell velocity distribution, rendering the PRW model invalid. Here we present a protocol for the analysis of 3D cell motility using the anisotropic PRW model. The software, which is implemented in MATLAB, enables statistical profiling of experimentally observed 2D and 3D cell trajectories, and it extracts the persistence and speed of cells along primary and nonprimary directions and an anisotropic index of migration. Basic computer skills and experience with MATLAB software are recommended for successful use of the protocol. This protocol is highly automated and fast, taking <30 min to analyze trajectory data per biological condition.

  8. A 3D contact analysis approach for the visualization of the electrical contact asperities

    DOE PAGES

    Roussos, Constantinos C.; Swingler, Jonathan

    2017-01-11

    The electrical contact is an important phenomenon that should be given into consideration to achieve better performance and long term reliability for the design of devices. Based upon this importance, the electrical contact interface has been visualized as a “3D Contact Map” and used in order to investigate the contact asperities. The contact asperities describe the structures above and below the contact spots (the contact spots define the 3D contact map) to the two conductors which make the contact system. The contact asperities require the discretization of the 3D microstructures of the contact system into voxels. A contact analysis approachmore » has been developed and introduced in this paper which shows the way to the 3D visualization of the contact asperities of a given contact system. For the discretization of 3D microstructure of contact system into voxels, X-ray Computed Tomography (CT) method is used in order to collect the data of a 250 V, 16 A rated AC single pole rocker switch which is used as a contact system for investigation.« less

  9. A 3D contact analysis approach for the visualization of the electrical contact asperities

    PubMed Central

    Swingler, Jonathan

    2017-01-01

    The electrical contact is an important phenomenon that should be given into consideration to achieve better performance and long term reliability for the design of devices. Based upon this importance, the electrical contact interface has been visualized as a ‘‘3D Contact Map’’ and used in order to investigate the contact asperities. The contact asperities describe the structures above and below the contact spots (the contact spots define the 3D contact map) to the two conductors which make the contact system. The contact asperities require the discretization of the 3D microstructures of the contact system into voxels. A contact analysis approach has been developed and introduced in this paper which shows the way to the 3D visualization of the contact asperities of a given contact system. For the discretization of 3D microstructure of contact system into voxels, X-ray Computed Tomography (CT) method is used in order to collect the data of a 250 V, 16 A rated AC single pole rocker switch which is used as a contact system for investigation. PMID:28105383

  10. Analysis of scalability of high-performance 3D image processing platform for virtual colonoscopy

    NASA Astrophysics Data System (ADS)

    Yoshida, Hiroyuki; Wu, Yin; Cai, Wenli

    2014-03-01

    One of the key challenges in three-dimensional (3D) medical imaging is to enable the fast turn-around time, which is often required for interactive or real-time response. This inevitably requires not only high computational power but also high memory bandwidth due to the massive amount of data that need to be processed. For this purpose, we previously developed a software platform for high-performance 3D medical image processing, called HPC 3D-MIP platform, which employs increasingly available and affordable commodity computing systems such as the multicore, cluster, and cloud computing systems. To achieve scalable high-performance computing, the platform employed size-adaptive, distributable block volumes as a core data structure for efficient parallelization of a wide range of 3D-MIP algorithms, supported task scheduling for efficient load distribution and balancing, and consisted of a layered parallel software libraries that allow image processing applications to share the common functionalities. We evaluated the performance of the HPC 3D-MIP platform by applying it to computationally intensive processes in virtual colonoscopy. Experimental results showed a 12-fold performance improvement on a workstation with 12-core CPUs over the original sequential implementation of the processes, indicating the efficiency of the platform. Analysis of performance scalability based on the Amdahl's law for symmetric multicore chips showed the potential of a high performance scalability of the HPC 3DMIP platform when a larger number of cores is available.

  11. New technologies of 2-D and 3-D modeling for analysis and management of natural resources

    NASA Astrophysics Data System (ADS)

    Cheremisina, E. N.; Lyubimova, A. V.; Kirpicheva, E. Yu.

    2016-09-01

    For ensuring technological support of research and administrative activity in the sphere of environmental management a specialized modular program complex was developed. The special attention in developing a program complex is focused to creation of convenient and effective tools for creation and visualization 2d and 3D models providing the solution of tasks of the analysis and management of natural resources.

  12. Application of 3D X-ray CT data sets to finite element analysis

    SciTech Connect

    Bossart, P.L.; Martz, H.E.; Brand, H.R.; Hollerbach, K.

    1995-08-31

    Finite Element Modeling (FEM) is becoming more important as industry drives toward concurrent engineering. A fundamental hindrance to fully exploiting the power of FEM is the human effort required to acquire complex part geometry, particularly as-built geometry, as a FEM mesh. Many Quantitative Non Destructive Evaluation (QNDE) techniques that produce three-dimensional (3D) data sets provide a substantial reduction in the effort required to apply FEM to as-built parts. This paper describes progress at LLNL on the application of 3D X-ray computed tomography (CT) data sets to more rapidly produce high-quality FEM meshes of complex, as-built geometries. Issues related to the volume segmentation of the 3D CT data as well as the use of this segmented data to tailor generic hexahedral FEM meshes to part specific geometries are discussed. The application of these techniques to FEM analysis in the medical field is reported here.

  13. Numerical Investigation of 3D multichannel analysis of surface wave method

    NASA Astrophysics Data System (ADS)

    Wang, Limin; Xu, Yixian; Luo, Yinhe

    2015-08-01

    Multichannel analysis of surface wave (MASW) method is an efficient tool to obtain near-surface S-wave velocity, and it has gained popularity in engineering practice. Up to now, most examples of using the MASW technique are focused on 2D models or data from a 1D linear receiver spread. We propose a 3D MASW scheme. A finite-difference (FD) method is used to investigate the method using linear and fan-shaped receiver spreads. Results show that the 3D topography strongly affects propagation of Rayleigh waves. The energy concentration of dispersion image is distorted and bifurcated because of the influence of free-surface topography. These effects are reduced with the 3D MASW method. Lastly we investigate the relation between the array size and the resolution of dispersion measurement.

  14. A Review of Failure Analysis Methods for Advanced 3D Microelectronic Packages

    NASA Astrophysics Data System (ADS)

    Li, Yan; Srinath, Purushotham Kaushik Muthur; Goyal, Deepak

    2016-01-01

    Advanced three dimensional (3D) packaging is a key enabler in driving form factor reduction, performance benefits, and package cost reduction, especially in the fast paced mobility and ultraportable consumer electronics segments. The high level of functional integration and the complex package architecture pose a significant challenge for conventional fault isolation (FI) and failure analysis (FA) methods. Innovative FI/FA tools and techniques are required to tackle the technical and throughput challenges. In this paper, the applications of FI and FA techniques such as Electro Optic Terahertz Pulse Reflectometry, 3D x-ray computed tomography, lock-in thermography, and novel physical sample preparation methods to 3D packages with package on package and stacked die with through silicon via configurations are reviewed, along with the key FI and FA challenges.

  15. 3D city models for CAAD-supported analysis and design of urban areas

    NASA Astrophysics Data System (ADS)

    Sinning-Meister, M.; Gruen, A.; Dan, H.

    A joint research project was conducted at ETH Zurich to develop a user-friendly software environment for the representation, visual manipulation, analysis and design of urban areas. Three groups were involved in the project: (1) the 'Architecture and Planning' group defined the requirements and expectations for the system; (2) the 'Photogrammetry' group acquired and processed raster and 3D vector data to form a 3D model of the urban area; and (3) the 'CAAD' (Computer Aided Architectural Design) group embedded the data into AutoCAD and implemented database functionality. Results of the photogrammetry group are presented, including the implementation of a 'topology builder' which automatically fits roof planes to manually or semi-automatically measured roof points in order to create AutoCAD-compatible 3D building models. Digital orthoimages and derived products such as perspective views, and the geometric correction of house roofs in digital orthoimages also were generated for test sites in Switzerland.

  16. A 3-D model of superfluid helium suitable for numerical analysis

    SciTech Connect

    Darve, C.; Patankar, N.A.; Van Sciver, S.W.; /Natl. High Mag. Field Lab.

    2008-01-01

    The two-fluid description is a very successful phenomenological representation of the properties of Helium II. A 3-D model suitable for numerical analysis based on the Landau-Khalatnikov description of Helium II is proposed. In this paper we introduce a system of partial differential equations that is both complete and consistent as well as practical, to be used for a 3-D solution of the flow of Helium II. The development of a 3-D numerical model for Helium II is motivated by the need to validate experimental results obtained by observing the normal component velocity distribution in a Helium II thermal counter-flow using the Particle Image Velocimetry (PIV) technique.