QSAR and docking studies on chalcone derivatives for antitubercular activity against M. tuberculosis H37Rv

In our prior studies, we reported some known antitubercular drugs (rifampicin and streptomycin) and newly synthesized chalcone derivatives (16–26) tested in vitro against Mycobacterium tuberculosis H₃₇Rv strain. Most of the tested compounds were efficient antimycobacterial agents showing minimum inhibitory concentration values ranging from 3.5 to 30 µg mL⁻¹. In the present work, a quantitative structure–activity relationship (QSAR) study has been performed on these active chalcone derivatives to correlate their chemical structures with their observed inhibiting activity against M. tuberculosis. A QSAR model that is able to correlate well the antitubercular activity with the chemical structures of active chalcone derivatives 16, 24, 25a, 25c, and 26 has been developed, which is potentially helpful in the design of novel and more potent antitubercular agents. The r² and rCV² of a newly derived QSAR model were 0.89 and 0.84, respectively. The QSAR study indicates that chemical properties, viz. heat of formation (kcal mol⁻¹), lowest unoccupied molecular orbital energy (eV), and amine, hydroxyl, and methyl groups counts, correlate well with the activity. In silico screening results for oral bioavailability and absorption, distribution, metabolism, excretion, and toxicity compliance showed that compounds 25a, 25c, and 24 were found active similar to rifampicin and streptomycin. The docking study for the exploration of mechanism of action showed high binding affinity of active derivatives. Copyright © 2014 John Wiley & Sons, Ltd.     

1,3-Oxazole derivatives of cytisine as potential inhibitors of glutathione reductase of Candida spp.: QSAR modeling,docking analysis and experimental study of new anti-Candida agents

Natural products as well as their derivatives play a significant role in the discovery of new biologically active compounds in the different areas of our life especially in the field of medicine. The synthesis of compounds produced from natural products including cytisine is one approach for the wider use of natural substances in the development of new drugs. QSAR modeling was used to predict and select of biologically active cytisine-containing 1,3-oxazoles. The eleven most promising compounds were identified, synthesized and tested. The activity of the synthesized compounds was evaluated using the disc diffusion method against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. Molecular docking of the most active compounds as potential inhibitors of the Candida spp. glutathione reductase was performed using the AutoDock Vina. The built classification models demonstrated good stability, robustness and predictive power. The eleven cytisine-containing 1,3-oxazoles were synthesized and their activity against Candida spp. was evaluated. Compounds 10, 11 as potential inhibitors of the Candida spp. glutathione reductase demonstrated the high activity against C. albicans M 885 (ATCC 10,231) strain and clinical fluconazole-resistant Candida krusei strain. The studied compounds 10, 11 present the interesting scaffold for further investigation as potential inhibitors of the Candida spp. glutathione reductase with the promising antifungal properties. The developed models are publicly available online at http://ochem.eu/article/120720 and could be used by scientists for design of new more effective drugs.     

Molecular structural investigations of quinoxaline derivatives through 3D-QSAR,molecular docking,ADME prediction and pharmacophore modeling studies for the search of novel antimalarial agent

In the present article, a dataset of 63 quinoxaline derivatives were taken for antimalarial activity and pharmacophore were developed. Atom based method was used to develop a three dimensional quantitative structure activity relationship (3D-QSAR) model. On comparison of all statistical parameters, model AHRRR23 was found to be the most effective and predictive QSAR model as it satisfied all statistical parameters of a good model. The model AHRRR23 showed an adequate R² value for the training set 0.9446, good predictive power with Q² of 0.6409, good F- value, low SD 0.1218 value and outstanding Pearson-R values and low RMSE 0.2779 values of the model. The docking studies also gives very good results with good RMSD values. 3D QSAR, docking and ADME studies exhibits that the developed model could be employed as a potential lead for further study as antimalarial drug.     

1,3-Oxazole-isoniazid hybrids: Synthesis,antitubercular activity,and their docking studies

A series of novel N′-([2-aryl-5-methyl-1,3-oxazole-4-yl]methylene)isonicotino/nicotino hydrazides 10a-l were prepared by the condensation reaction of 2-aryl-5-methyl-1,3-oxazole-4-carbaldehydes 8a-f with the corresponding isonicotino/nicotino hydrazides 9a/9b . The structures of the new compounds were elucidated by various spectroanalytical techniques, including IR, ¹H NMR, ¹³C NMR, elemental (C,H,N), and mass analysis. All the newly prepared INH-1,3-oxazole hybrids were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. Among all the synthesized hybrids, compounds 10c and 10i derivatives displayed highest antitubercular activity with minimal inhibitory concentration 1.56 μg/mL. Further, molecular docking studies against the InhA enzyme were carried out to understand the interactions between potent hybrids and the target enzyme. Thus, these kind hybrids have the potentiality for the discovery of new antitubercular agents for deployment in the control and eradication of tuberculosis.     

3D-QSAR,docking, molecular dynamics simulation and free energy calculation studies of some pyrimidine derivatives as novel JAK3 inhibitors

Janus kinase 3 (JAK3) is a promising drug target for the treatment of inflammatory diseases, autoimmune disorders, organ transplant rejection and various cancers. In the present study, 3D-QSAR, docking, MD simulation and MM/PBSA studies were performed on a series of pyrimidine-based JAK3 inhibitors. A reliable COMSIA (q² = 0.717 and r² = 0.986) model was developed and validated using external validation test set, bootstrapping, progressive scrambling and r_m² metrics analyses. Structural requirements identified through contour maps of the model were strategically utilized to computationally design 170 novel JAK3 inhibitors with improved potency. Docking studies were performed on the selected data set and newly designed compounds to show their binding mode and to identify important interacting residues inside the active site of JAK3. In addition, docking results of the selected designed compounds inside the active sites of JAK1, JAK2 and TYK2 indicated their JAK3 selectivity. MD simulation (100 ns) on the docked complex of compound 28 (one of highly active compounds of the data set) assisted in the further exploration of the binding interactions. Some crucial residues like Lys830 (glycine-rich loop), Val836, Ala853, Leu905 (hinge region), Cys909, Asn954, Leu956 and Ala966 were identified. Hydrogen bond interactions with hinge residue Leu905 were critical for the binding of JAK3 inhibitors. Additionally, MM/PBSA calculation provided the binding free energy of the compound 28. Newly designed molecules showed promising results in the preliminary in silico ADMET evaluations. Outcomes of the study can further be exploited to develop potent JAK3 inhibitors.     

Towards further understanding the structural insights of isoxazoles analogues against leishmaniasis using QSAR,molecular docking and molecular dynamics model

Leishmaniasis is one of the most well-known neglected infectious diseases, which is severe problem for public health. Heterocyclic derivatives are known to displays wide range of pharmacology activities including isoxazole ring that exhibit antileishmanial activity. Quantitative structure-activity relationship (QSAR) molecular docking and molecular dynamics are computational approaches to identify the relationships between structural properties and binding affinity of compounds. In the given paper series of 59, 4-aminomethyl 5-aryl-3-substituted isoxazoles were used to identify the structural insights and to find the binding affinity with protein. The designed model produced statistically significant results with of R² = 0.72, R²_adj = 0.65, and Q²_LMO = 0.72. Structure activity relationship (SAR) revealed that substitution of hydrophobic and steric groups may enhance the biological activity of compounds as antiprotozoal agents. Most potent compound formed hydrogen bonds with active amino acids Arg 87, Arg 104, Gly 112, His 117, Gly 118 and Asp 120. Molecular dynamics simulation (150 ns) on the docked complex of most active compound 3ba and 6 ab supported in the exploration of binding. Further MMPBSA investigations utilising MD trajectories verified compound 3bc higher binding affinity for nucleoside diphosphate kinases. The given strategies of computational studies could be an encouraging way for designing therapeutic targets against leishmaniasis.     

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

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.     

Application to QSAR studies of 2-furylethylene derivatives

A quantitative structure–activity relationship (QSAR) is a mathematical model that relates a molecular structure to a physicochemical property or a biological activity. The log P of a set of 38 of 2-furylethylenes, biologically active substances exhibiting a broad spectrum of antimicrobial, antiparasitic, cytotoxic, carcinogenic and mutagenic activities, was modeled by using topological indices provided by TOPOCLUJ and DRAGON software packages. The models derived showed good stability and predictability (as given by the leave-one-out LOO cross-validation data). The results are compared with those reported in literature, obtained by different methodology.     

Synthesis,antimicrobial activity and QSAR studies of 2,5-disubstituted benzoxazoles

In this study, a new series of 2,5-disubstituted benzoxazoles was synthesized and their structures were elucidated by elemental analysis, MASS, ¹H-NMR, ¹³C-NMR and IR spectral data. Newly and previously synthesized 2,5-disubstituted benzoxazole derivatives were evaluated for antibacterial and antifungal activity against standard strains and their drug-resistant isolates. Microbiological results showed that the compounds presented a large spectrum of activity having MIC values of 250–7.8 µg mL^?1 against the tested microorganisms. Among the newly synthesized derivatives 3–22, compound 11 was the most active against Candida krusei out of all; however, it was one dilution less potent than standard drug fluconazole. In addition, all the new and previous compounds were more active than standard drugs ampicillin trihydrate and rifampicin against Pseudomonas aeruginosa and its gentamicin-resistant isolate. The 2D-QSAR (Quantitative Structure–Activity Relationship) analysis of a set of newly and previously synthesized benzoxazoles tested for growth inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) was also performed by using multivariable regression analysis. The activity contributions for substituent effects of these compounds were determined from the correlation equation for predictions of the lead optimization.     

QSAR based modeling of inhibitory activity of alkenyldiarylmethane derivatives

A series of alkenyldiarylmethanes (ADAMs) were subjected to QSAR analysis by using linear free energy relationship model of Hansch. QSAR has been developed using steric, electronic and topological parameters along with appropriate dummy variable. Statistical techniques were applied to identify the structural and physicochemical requirements for ADAMs. The results are critically discussed on the basis of regression data and cross-validation techniques.     

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

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.     

Synthesis,anticancer, molecular docking and QSAR studies of benzoylhydrazone

To find out effective anticancer compounds we synthesized (1–30) derivatives of 4-isopropylbenzoylhydrazone and evaluated for anticancer potential. The compounds 3, 9, 12, 23, 26 and 28 showed better activities ranging (0.39–1.1 µg/ml) than the standard (1.53 ± 0.01 µg/ml). In line with this, compounds 2, 6, 24, 25 and 29 exhibited better activities compared to the second standard (5FU 4.60 ± 0.01 µg/ml). The best molecular docked complex between the BRCA1 structure and the 1–30 derivatives were analyzed based on the Glide docked score and binding orientation for both the SP and XP mode. The 2D-QSAR analysis reflected a significant correlation between the experimental and the predicted biological activities. The above-mentioned compounds were also assessed by various spectroscopic techniques.     

Synthesis,anti-tuberculosis activity and QSAR study of 2,4-diarylquinolines and analogous polycyclic derivatives

The multicomponent syntheses of 2,4-di-aryl-quinolines and analogous polycyclic derivatives as anti-tuberculosis agents were described. They were prepared via Beyer and Friedländer methods under microwave irradiation in short reaction times and good yields. Several homogeneous and heterogeneous acid catalysts were compared for preparing 2,4-di-arylquinolines and among them trifluoroacetic acid (TFA) reached the higher yields. Two derivatives exhibited activity against Mycobacterium tuberculosis H37Rv (Mtb), underwent additional testing and were considered lead compounds. The synthesis of a series of polycyclic analogous led to six new active compounds and a Quantitative Structure Activity Relationship study (QSAR) study was established.     

Synthesis,cytotoxicity, apoptosis and molecular docking studies of novel phenylbutyrate derivatives as potential anticancer agents

Phenylbutyrate (PB), a small aromatic fatty acid, has been known as an interesting compound with the ability of anti-proliferation and cell growth inhibition in cancer cells. In the present study, a series of PB derivatives were synthesized by Passerini multicomponent reaction and their cytotoxic activities against various human cancer cell lines including A549 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SW1116 (colon cancer) were evaluated. The results revealed that B9, displayed significantly higher in vitro cytotoxicity with IC₅₀ of 6.65, 8.44 and 24.71 μM, against A549, MDA-MB-231 and, SW1116, respectively, in comparison to PB. The effects of these compounds on the proliferation of MCF-10A as non-tumoral breast cell line, showed good selectivity of the compounds between tumorigenic and non-tumorigenic cell lines. Moreover, B9 has indicated apoptosis-inducing activities to MDA-MB-231 cancer cell line in a dose-dependent manner. The molecular docking studies of the synthesized compounds on pyruvate dehydrogenase kinase 2 (PDK2; PDB ID: 2BU8) and histone deacetylase complex (HDAC; PDB ID: 1C3R), as the main targets of PB were applied to predict the binding sites and binding orientation of the compounds to these targets.