Comparative Molecular Field Analysis Studies Research Articles

Comparative Molecular Field Analysis (CoMFA), Molecular Docking and ADMET Study on Thiazolidine-4-carboxylic acid Derivatives as New Neuraminidase Inhibitors

The objective of this research was to create a 3D-QSAR CoMFA model for a set of twenty-five neuraminidase inhibitors containing thiazolidine-4-carboxylic acid derivatives and to identify a new potent neuraminidase inhibitor for the treatment of influenza. The statistical parameters of the generated model are excellent: Q2 = 0.708, R2 = 0.997. The external validation results were (r2 0 = 0.922, K= 1.016, R2 pred = 0.674, r2 m= 0.778) indicating that the constructed model has good predictive power. Based on the contour map of the CoMFA model, we were able to propose six novel compounds with higher neuraminidase inhibitory activity than the most active compound. The six proposed molecules were submitted to molecular docking to analyse the bindings formed between the newly designed molecules and the neuraminidase. All of the proposed molecules were found to be more stable on the active site of neuraminidase than the reference molecule (1SJ). SwissADME was used to estimate the pharmacokinetic properties of each proposed molecule, while ProToxII and VEGA QSAR were used to investigate any potential toxicity. Finally, a reaction mechanism for synthesizing the six proposed compounds was described, which could potentially be explored further in the search for novel neuraminidase inhibitors. In conclusion, this study has identified potential candidates for the development of more effective neuraminidase inhibitors for the treatment of influenza.

CoMFA INVESTIGATION FOR A SERIES OF PRENYL-ALKYLATED BIS-1,2,4-TRIAZOLES

Predictive strategies and approaches are now widely used by scientists in molecular biology and chemistry for the synthetic design of potentially active compounds.
 Comparative molecular field analysis (CoMFA) is a technique for determining three-dimensional quantitative structure-activity relationships (3D QSAR). According to the methodology, it is necessary to choose the bioactive conformation of each studied compound, and all structures are superimposed. According to the results, mapping was carried out and thus the steric and electrostatic fields of these molecules are calculated, which makes possible to evaluate further favorable ways for functionalization of the tested substances.
 The 1,2,4-triazole fragment is a proven valuable component in medicine, as it is part of a number of medicines, and in recent works we have also proven their high biological effect and predicted ways of using condensed and functional derivatives.
 In the framework, we conducted the synthesis of prenyl-alkylated bis-1,2,4-triazoles and CoMFA studies with the aim of evaluating directions for further synthetic design and functionalization of the target compounds to increase their valuable bioproperties.
 Keywords: bis-1,2,4-triazole; alkylation; CoMFA; bioactivity.

New dehydroabietic acid (DHA) derivatives with anticancer activity against HepG2 cancer cell lines as a potential drug targeting EGFR kinase domain. CoMFA study and virtual ligand-based screening

Liver cancer has become the third type of cancer that causes death; this is why the design of new chemotherapeutic drugs against this disease is a major need. With this idea, a series of Dehydroabietic Acid-Based Acylhydrazones have been used to generate a CoMFA model to design new anticancer agents. In this study, we employed a Comparative Molecular Field Analysis studies, we performed those methods on Dehydroabietic Acid-Based Acylhydrazones against HepG2 human cancer cell line. The statistical results are encouraging with Q2 equal to 0.527 and R2 equal to 0.962. The predictive ability of this model was determined using a test set of Dehydroabietic Acid-Based Acylhydrazones that gave an acceptable predictive correlation (R2test) value of 0.614. The developed model guides to design five new molecules with enhanced activity as potential drugs. On the other hand to determine a potential target to these ligands we have established a virtual screening using reverse docking with the most active molecule and 42 antiproliferative targets. Based on the affinity of complex ligand-Target, the intracellular domain of EGFR shows high stability. This suggests that our designed molecules can inhibit the target EGFR which is an important target on targeted therapy of many types of cancer. Communicated by Ramaswamy H. Sarma

Towards the In-silico Design of New HSP90 Inhibitors: Molecular Docking and 3D-QSAR CoMFA Studies of Tetrahydropyrido [4, 3-d] Pyrimidine Derivatives as HSP90 Inhibitors.

HSP90 is necessary for the conformational maturation of proteins, proteins disaggregation, folding newly synthesized peptides and the refolding of denatured proteins. The inhibition of HSP90 leads to proteasomal degradations of client proteins that finally kill cancer cells. In this research, molecular docking and comparative molecular field analysis (CoMFA) were used to investigate the interactions of tetrahydropyrido[4,3-d]pyrimidine derivatives with the N-terminal domain binding site of the HSP90 and predicting their inhibitory activities. A CoMFA model with five components and q2 of 0.81 was developed. R2 for training and test sets were 0.96 and 0.79, respectively. Based on extracted Contour maps for this CoMFA model, three new inhibitors with greater pIC50 with respect to the greatest active molecule in the data-set were designed by modifying molecule m45. Molecule m45 and designed inhibitors were docked to the N-terminal domain binding site of the HSP90. Designed inhibitors obtained lower binding energy with respect to m45. Based on extracted CoMFA contour maps, bulky substituents are favored for the R1 group and in R3 group, short and bulky substituents increase the activity of molecules. Less bulky and longer substituents are favored for R2. The molecular docking analysis of compound m45 with the N-terminal domain binding site of the HSP90 show hydroxyl group on phenyl ring is necessary to form hydrogen bonding with hydrophilic residues in binding site and a conserved water molecule. Molecule m45 has Pi-Sigma interaction with phenyl ring in the side chain of Phenylalanine 138 via isopropyl substituent on meta position of the phenyl ring. Also, Molecule m45 forms carbon-hydrogen bond with oxygen atoms at the side chain of Aspartic acid 54 and Asparagine 51 via its dimethylamine group. Others are Van der Waals interactions.

Comparative molecular field analysis and hologram quantitative structure activity relationship studies of pyrimidine series as potent phosphodiesterase 10A inhibitors

The inhibition of phosphodiesterase (PDE) 10A enzyme as an alternative approach is shown to have potential in the current treatment of schizophrenia. In the present work, the inhibition activity of 87 structurally diverse pyrimidine derivatives as PDE10A inhibitors were subjected to 2‐dimensional quantitative structure activity relationship (2D‐QSAR) and 3D‐QSAR studies using hologram QSAR and comparative molecular field analysis (CoMFA), respectively. The best CoMFA model gave a noncross‐validated correlation coefficient, () = 0.977, SEtrain = 0.247 and predictive correlation coefficient () = 0.957, and SEtest = 0.358. For the hologram QSAR (HQSAR) model, the similar parameters were , SEtrain = 0.565, , and SEtest = 0.872. The leave‐one‐out (LOO) cross‐validated r2 (q2) were 0.78 and 0.8 for the CoMFA and HQSAR models, respectively. These statistics indicate that the CoMFA model is more satisfactory than the HQSAR. Analysis of CoMFA steric and electrostatic contour maps strongly demonstrate that the presence of bulky group at the end of R1 substituent, especially heterocyclic aromatic rings, increase the inhibitory activities, and electronegative groups, such as alkoxide at the R2 position, enhance the inhibitory activities of studied chemicals. The results of this study serves as a guide for the possible modifications and designing of novel pyrimidine derivatives as new potent PDE10A inhibitors.

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

The wide tissue distribution of the adrenergic β3 receptor makes it a potential target for the treatment of multiple pathologies such as diabetes, obesity, depression, overactive bladder (OAB), and cancer. Currently, there is only one drug on the market, mirabegron, approved for the treatment of OAB. In the present study, we have carried out an extensive structure-activity relationship analysis of a series of 41 aryloxypropanolamine compounds based on three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques. This is the first combined comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) study in a series of selective aryloxypropanolamines displaying anti-diabetes and anti-obesity pharmacological profiles. The best CoMFA and CoMSIA models presented values of r2ncv = 0.993 and 0.984 and values of r2test = 0.865 and 0.918, respectively. The results obtained were subjected to extensive external validation (q2, r2, r2m, etc.) and a final series of compounds was designed and their biological activity was predicted (best pEC50 = 8.561).

Computer aided drug design based on 3D-QSAR and molecular docking studies of 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives as PIM2 inhibitors: a proposal to chemists.

PIM2 kinase plays a crucial role in the cell cycle events including survival, proliferation, and differentiation in normal and neoplastic neuronal cells. Thus, it is regarded as an essential target for cancer pharmaceutical. Design of novel 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amine derivatives with enhanced PIM2 inhibitory activity. A series of twenty-five PIM2 inhibitors reported in the literature containing 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines scaffold was studied by using 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 indexes analysis (CoMSIA) studies were developed using nineteen molecules having pIC50 ranging from 8.222 to 4.157. The best generated CoMFA and CoMSIA models exhibit conventional determination coefficients R2 of 0.91 and 0.90 as well as the Leave One Out cross-validation determination coefficients Q2 of 0.68 and 0.62, respectively. Moreover, the predictive ability of those models was evaluated by the external validation using a test set of six compounds with predicted determination coefficients Rtest 2 of 0.96 and 0.96, respectively. Besides, y-randomization test was also performed to validate our 3D-QSAR models. The most and the least active compounds were docked into the active site of the protein (PDB ID: 4 × 7q) to confirm those obtained results from 3D-QSAR models and elucidate the binding mode between this kind of compounds and the PIM2 enzyme. These satisfactory results are not offered help only to understand the binding mode of 5-(1H-indol-5-yl)-1,3,4-thiadiazol series compounds into this kind of targets, but provide information to design new potent PIM2 inhibitors.

Comparative molecular field analysis and molecular dynamics studies of the dopamine D2 receptor antagonists without a protonatable nitrogen atom

The dopaminergic hypothesis of schizophrenia is the main concept explaining the direct reasons of schizophrenia and the effectiveness of current antipsychotics. All antipsychotics present on the market are potent dopamine D2 receptor antagonists or partial agonists. In this work we investigate a series of dopamine D2 receptor antagonists which do not fulfill the criteria of the classical pharmacophore model as they do not possess a protonatable nitrogen atom necessary to interact with the conserved Asp(3.32). Such compounds are interesting, inter alia, due to possible better pharmacokinetic profile when compared to basic, ionizable molecules. By means of homology modeling, molecular docking and molecular dynamics we determined that the compounds investigated interact with Asp(3.32) via their amide nitrogen atom. It was found that the studied compounds stabilize the receptor inactive conformation through the effect on the ionic lock, which is typical for GPCR antagonists. We constructed a CoMFA model for the studied compounds with the following statistics: R2 = 0.95, Q2 = 0.63. The quality of the CoMFA model was confirmed by high value of R2 of the test set, equal 0.96. The CoMFA model indicated two regions where bulky substituents are favored and two regions where bulky substituents are not beneficial. Two red contour regions near carbonyl groups were identified meaning that negative charge would be favored here. Furthermore, the S-oxide group is connected with blue contour region meaning that positive charge is favored in this position. These findings may be applied for further optimization of the studied compound series.

Insights into the Structural Requirements of Potent Brassinosteroids as Vegetable Growth Promoters Using Second-Internode Elongation as Biological Activity: CoMFA and CoMSIA Studies.

In the present study, we have employed the ligand-based drug design technique, 3D-QSAR, through a comparative molecular field analysis (CoMFA) and a comparative molecular similarity indices analysis (CoMSIA) to determine the key factors for the plant growth promoting activity of brassinosteroids reported in literature, using the bean second-internode bioassay measured on two groups of compounds with different molar concentrations. This is the first 3D-QSAR study using the second internode elongation as biological activity. These results provide useful ideas for the design of new molecules, which could be explored in the future to identify novel vegetable growth promoters with similar or greater biological activity than natural brassinosteroids. The reliability of this study was supported by the robust statistical parameters obtained from CoMFA (Model A, r2pred = 0.751; Model B, r2pred = 0.770) and CoMSIA (Model A, r2pred = 0.946; Model B, r2pred = 0.923) analysis.

Combined HQSAR, topomer CoMFA, homology modeling and docking studies on triazole derivatives as SGLT2 inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) is a promising target for diabetes therapy. We aimed to develop computational approaches to identify structural features for more potential SGLT2 inhibitors. In this work, 46 triazole derivatives as SGLT2 inhibitors were studied using a combination of several approaches, including hologram quantitative structure-activity relationships (HQSAR), topomer comparative molecular field analysis (CoMFA), homology modeling, and molecular docking. HQSAR and topomer CoMFA were used to construct models. Molecular docking was conducted to investigate the interaction of triazole derivatives and homology modeling of SGLT2, as well as to validate the results of the HQSAR and topomer CoMFA models. The most effective HQSAR and topomer CoMFA models exhibited noncross-validated correlation coefficients of 0.928 and 0.891 for the training set, respectively. External predictions were made successfully on a test set and then compared with previously reported models. The graphical results of HQSAR and topomer CoMFA were proven to be consistent with the binding mode of the inhibitors and SGLT2 from molecular docking. The models and docking provided important insights into the design of potent inhibitors for SGLT2.

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

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 (rpred2 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.

Molecular docking and CoMFA studies of thiazoloquin(az)olin(on)es as CD38 inhibitors: determination of inhibitory mechanism, pharmacophore interactions, and design of new inhibitors

In this research, molecular docking and 3D-QSAR studies were carried out on a series of 79 thiazoloquin(az)olin(on)es as CD38 inhibitors. Based on docking results, four interactions including hydrogen bonding with main chain of GLU-226 (H-M-GLU-226), Van der Waals interactions with side chain of TRP-125 (V-S-TRP-125), TRP-189 (V-S-TRP-189), and THR-221 (V-S-THR-221) were considered as pharmacological interactions. Active conformation of each ligand was extracted from docking studies and was used for carrying out 3D-QSAR modeling. Comparative molecular field analysis (CoMFA) was performed on CD38 inhibitory activities of these compounds on human and mouse. We developed CoMFA models with five components as optimum models for both data-sets. For human data-set, a model with high predictive power was developed. R2, RMSE, and F-test values for training set of this model were .94, .24, and 179.58, respectively, and R2 and RMSE for its test set were .92 and .32, respectively. The q2 and RMSE values for leave-one-out cross validation test on training set were .78 and .46, respectively, that demonstrate created model is robust. Based on extracted steric and electrostatic contour maps for this model, three inhibitors with pIC50 larger than 8.85 were designed.

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

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q2) of 0.912 and the non-cross-validated correlation coefficient (r2) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r2 value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds.

3D-QSAR Studies on 2-(indol-5-yl)thiazole Derivatives as Xanthine Oxidase (XO) Inhibitors

Xanthine Oxidase is an enzyme, which oxidizes hypoxanthine to xanthine, and xanthine to uric acid. It is widely distributed throughout various organs including the liver, gut, lung, kidney, heart, brain and plasma. It is involved in gout pathogenesis. In this study, we have performed Comparative Molecular Field Analysis (CoMFA) on a series of 2-(indol-5-yl) thiazole derivatives as xanthine oxidase (XO) inhibitors to identify the structural variations with their inhibitory activities. Ligand based CoMFA models were generated based on atom-by-atom matching alignment. In atom-by-atom matching, the bioactive conformation of highly active molecule 11 was generated using systematic search. Compounds were aligned using the bioactive conformation and it is used for model generation. Different CoMFA models were generated using different alignments and the best model yielded a cross-validated of 0.698 with five components and non-cross-validated correlation coefficient () of 0.992 with Fisher value as 236.431, and an estimated standard error of 0.068. The predictive ability of the best CoMFA models was found to be 0.653. The CoMFA study revealed that the position of the structure is important in influencing the biological activity of the inhibitors. Electro positive groups and bulkier substituents in this position enhance the biological activity.

Comparative molecular field analysis and molecular dynamics studies of α/β hydrolase domain containing 6 (ABHD6) inhibitors.

The endocannabinoid system remains an attractive molecular target for pharmacological intervention due to its roles in the central nervous system in learning, thinking, emotional function, regulation of food intake or pain sensation, as well as in the peripheral nervous system, where it modulates the action of cardiovascular, immune, metabolic or reproductive function. α/β hydrolase domain containing 6 (ABHD6)—an enzyme forming part of the endocannabinoid system—is a newly discovered post-genomic protein acting as a 2-AG (2-arachidonoylglycerol) serine hydrolase. We have recently reported a series of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors. Here, we present comparative molecular field analysis (CoMFA) and molecular dynamics studies of these compounds. First, we performed a homology modeling study of ABHD6 based on the assumption that the catalytic triad of ABHD6 comprises Ser148–His306–Asp 278 and the oxyanion hole is formed by Met149 and Phe80. A total of 42 compounds was docked to the homology model using the Glide module from the Schrödinger suite of software and the selected docking poses were used for CoMFA alignment. A model with the following statistics was obtained: R2 = 0.98, Q2 = 0.55. In order to study the molecular interactions of the inhibitors with ABHD6 in detail, molecular dynamics was performed with the Desmond program. It was found that, during the simulations, the hydrogen bond between the inhibitor carbonyl group and the main chain of Phe80 is weakened, whereas a new hydrogen bond with the side chain of Ser148 is formed, facilitating the possible formation of a covalent bond.Graphical Left–right: Docking pose of 1 in the binding pocket of α/β hydrolase domain containing 6 (ABHD6) selected for molecular alignment; CoMFA steric and electrostatic contour fields; changes in potential energy of the complex during simulations for the complex of 6 and ABHD6Electronic supplementary materialThe online version of this article (doi:10.1007/s00894-015-2789-8) contains supplementary material, which is available to authorized users.

Molecular docking, 2D and 3D-QSAR studies of new indole-based derivatives as HCV-NS5B polymerase inhibitors

Hepatitis C virus (HCV) is a main cause of liver disease worldwide and a potential cause of considerable malady and mortality in the future. The docking and molecular dynamics simulation (MDs) have been carried out on a series of indole-based derivatives into the cavity of HCV-NS5B polymerase. The docking and MDs led to recognition of the best conformers of inhibitors and also determination of the key interacting amino acids of the binding site of the protein packet. In addition, the conformers are very similar to bioactive ones which in turn will guarantee the most reliable and predictive models in 2D and 3D-QSAR studies. To find the correlation between inhibitory activities of ligands against HCV-NS5B, a comparative molecular field analysis (CoMFA) study, as a 3D-QSAR method, was carried out and the corresponding contour maps of electrostatic and steric fields were computed. Furthermore, 2D descriptors were calculated utilizing the optimal conformers. In the case of 2D-QSAR, a variable selection was applied by genetic algorithm (GA), followed by model building using partial least squares (GA-PLS) and support vector machine (GA-SVM) regression methods. The predictive ability of the proposed models was validated by a structurally diverse test set of 22 compounds that had not been included in the training step. The q 2 and the $$r_{\text{pred}}^{2}$$ values for CoMFA, GA-PLS and GA-SVM models were 0.521, 0.655, and 0.746 and 0.659, 0.881, and 0.967, respectively. Moreover, the molecular interactions of these inhibitors with the HCV-NS5B’s active site residues were properly discussed.

Combined Autodock and comparative molecular field analysis study on predicting 5-lipoxygenase inhibitory activity of flavonoids isolated from Spatholobus suberectus Dunn.

5-Lipoxygenase (5-LOX) plays a key role in the pathway of leukotriene biosynthesis. To predict the inhibitory activity of flavonoid inhibitors against 5-LOX from Spatholobus suberectus Dunn, Autodock 4.2 and comparative molecular field analysis (CoMFA) were employed. For the positive inhibitors (n=7), the value of the coefficient of determination (R2) between the binding free energy, calculated using Autodock 4.2, and the experimental pIC50 is 0.838. In the training set (n=21) of inhibitors against 5-LOX, the R2 of non-cross-validated partial least squares analysis between the actual and predicted pIC50 values, using the no-validation with the optimum number of components set to 6, is 0.997 (p=0.000). For the model generated by CoMFA, the contribution of electrostatic and steric factors are 0.522 and 0.478, respectively. Among the flavonoids of S. suberectus, liquiritigenin, catechin, butin, 3',4',7-trihydroxyflavone, plathymenin, and gallocatechin are the more potent inhibitors of 5-LOX based on the calculated binding free energy and the predicted pIC50 value.

CoMFA, CoMSIA, kNN MFA and docking studies of 1,2,4-oxadiazole derivatives as potent caspase-3 activators

Caspase-3 has become an attractive target in the treatment of many diseases such as Alzheimer, Parkinson’s, myocardial infarction and cancer. In the present study, molecular three-dimensional quantitative structure activity relationship (3D-QSAR) and docking studies were performed on a series of caspase-3 activators. Comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and step-wise k-nearest neighboring molecular field analysis [(SW) kNN MFA] were performed to gain insight into the key structural factors affecting the activity. The results of 3D-QSAR are reliable and significant having high predictive (q2) ability showing good correlation between predicted and observed activity. The lower value of standard error of estimation shows that most of the observed values cluster fairly close to the regression line. Molecular docking was performed with the GOLD docking program used to explore the binding mode between the ligands and the receptor.

The discovery of potentially selective human neuronal nitric oxide synthase (nNOS) Inhibitors: a combination of pharmacophore modelling, CoMFA, virtual screening and molecular docking studies.

Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow for the identification and prioritization of compounds as potentially selective human nNOS inhibitors. Three-dimensional pharmacophore models were constructed based on a set of known nNOS inhibitors. The pharmacophore models were evaluated by Pareto surface and CoMFA (Comparative Molecular Field Analysis) analyses. The best pharmacophore model, which included 7 pharmacophore features, was used as a search query in the SPECS database (SPECS®, Delft, The Netherlands). The hit compounds were further filtered by scoring and docking. Ten hits were identified as potential selective nNOS inhibitors.

CoMFA and docking study of 2,N6-disubstituted 1,2-dihydro-1,3,5-triazine-4,6-diamines as novel PfDHFR enzyme inhibitors for antimalarial activity

A three-dimensional quantitative structure–activity relationship (3D-QSAR) study was performed on 1,3,5-triazine derivatives which were based on Ala16Val+Ser108Thr mutant DHFR inhibitors of Plasmodium falciparum clone (FCR-3). Comparative Molecular Field Analysis (CoMFA) was carried out for designing novel PfDHFR enzyme inhibitors. It is shown that the steric and electrostatic properties by CoMFA contours can be related to the PfDHFR inhibitory activity. Glide-XP of Schrödinger was used for docking of PfDHFR inhibitors into the putative binding sites of the PfDHFR.