Publications by authors named "Vijjulatha Manga"

37 Publications

Integrated computational approach for design of new purinyl pyridine derivatives as B-Raf kinase inhibitors.

J Recept Signal Transduct Res 2021 Nov 29:1-15. Epub 2021 Nov 29.

Department of Chemistry, University College of Science, Osmania University, Hyderabad, India.

B-Raf is one among the most frequently mutating proto-oncogene which is associated with the serine/threonine Raf kinase family involved in the RAS-RAF-MEK-ERK pathway, which is the most deregulated pathway in human cancers. Mutant B-Raf got an excellent scope for investigation in cancer as a potential therapeutic target. Formerly B-Raf is considered the molecular target for numerous antitumor compounds like purinyl pyridine and pyrimidine derivatives. In the current research work using molecular docking approach of Schrodinger Glide 5.6 version, ligand docking, pharmacophore-based virtual screening, binding free energy calculations of a series of 2-amino purinyl pyridine and pyrimidine derivatives were modeled, their docking values were predicted, that were considered to be potent against B-Raf . A five-point hypothesis accompanied by a hydrogen bond acceptor(A), two hydrogen bond donors(D), and two aromatic rings (R) was built with a justifiable R value of 0.91 and a Q value of 0.64. Then by using Asinex Elite Synergy database, virtual screening was performed, and identified several potential hits. Subsequently, the molecules which had interactions with the target B-Raf kinase were determined by subjecting the obtained hits for SP and XP docking processes. Finally, for the top leads obtained, binding free energies were accomplished. About 16 new purinyl pyridine molecules were also designed. Almost nine molecules manifested crucial ligand interactions and binding free energies. At the outset, this research paved the way for us in spotting new molecules with B-Raf inhibitory activity, which can further be explored to design molecules with enhanced pharmacokinetic profiles.
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http://dx.doi.org/10.1080/10799893.2021.1999472DOI Listing
November 2021

Synthesis, antitubercular, antimicrobial activities and molecular docking study of quinoline bearing dihydropyrimidines.

Bioorg Chem 2021 10 15;115:105173. Epub 2021 Jul 15.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad 500007, Telangana, India.

In order to develop the antimicrobial and antitubercular agents, we have derived quinoline bearing dihydropyrimidine analogues 5a-o and structures of these compounds were determined by spectroscopic techniques. Further, we have calculated the molecular properties prediction and drug-likeness by Molinspiration property calculation toolkit and MolSoft software, respectively. The most active compound against Mycobacterium tuberculosis (5m, MIC = 0.20 µg/mL) also possessed a maximum drug-likeness model score (0.42). Compounds 5m, 5g and 5k were possessed promising antibacterial activity against tested bacterial species. Compound 5k was the only compound to have eye-catcher antifungal activity. Furthermore, the MTT cytotoxicity results on HeLa cells suggested lower cytotoxicity of biologically active compounds. Supramolecular interactions of the synthesized compounds has been assessed my means of molecular docking studies. Although all the synthesized compounds are showing preferably good interactions with their respective proteins, their binding free energies values suggest that these molecules are preferred for antitubercular activity rather than antimicrobial activity.
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http://dx.doi.org/10.1016/j.bioorg.2021.105173DOI Listing
October 2021

Design and synthesis of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-diones: a potential cytotoxic scaffolds and their molecular modeling studies.

Mol Divers 2021 Nov 2;25(4):2017-2033. Epub 2020 May 2.

Molecular Modeling and Medicinal Chemistry Laboratory, Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500 007, India.

In an effort to discover potential cytotoxic agents, a series of novel (Z)-5-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)-3-((1-substituted phenyl-1H-1,2,3-triazol-4-yl)methyl)thiazolidine-2,4-dione derivatives (8a-n) were designed and synthesized in various steps with acceptable reaction procedures with quantitative yields and characterized by H NMR, C NMR, IR, HRMS and ESI-MS spectra. These newly synthesized novel derivatives were screened for their in vitro cell viability/cytotoxic studies against human breast cancer cell line (MCF-7) with various concentrations of 0.625 µM, 1.25 µM, 2.5 µM, 5 µM and 10 µM, respectively. The biological interpretation assay outcome was demonstrated in terms of cell viability percentage reduction and IC values against standard reference drug cisplatin. Based on these results, most of the derivatives exhibited promising cytotoxic activity. Among them, particularly compounds 8j (R = OMe and R = NO) and 8e (R = CF) demonstrate remarkable cytotoxic activity with IC values 0.426 µM ± 0.455 and 0.608 µM ± 0.408, which are even better than the standard drug cisplatin 0.636 µM ± 0.458 and compounds 8m (R = OMe and R = OMe) and 8c (R = OMe) exhibited closely equivalent IC values to the standard drug with IC values 0.95 µM ± 0.32 and 0.976 µM ± 0.313 and rest of the compounds exhibits moderate cytotoxic activity. Moreover, molecular modeling studies and ADME calculations of the novel synthesized derivatives are in adequate consent with the pharmacological screening results.
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http://dx.doi.org/10.1007/s11030-020-10093-3DOI Listing
November 2021

Integrated molecular docking, 3D QSAR and molecular dynamics simulation studies on indole derivatives for designing new Pim-1 inhibitors.

J Recept Signal Transduct Res 2020 Feb 13;40(1):1-14. Epub 2020 Jan 13.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad, India.

Pim-1 is one of the isoforms of pim proteins comprising pim-1, pim-2 and pim-3. It was basically recognized as proviral integration moloney murine leukemia virus which is associated with T-cell lymphomogenesis. Pim-1 is known to play a crucial role in cell cycle progression and acts as downstream target for the JAK/STAT signaling pathway. Recently it has emerged as a hopeful therapeutic target for cancer treatment as deregulation or over expression of pim causes hematologic cancers. In present article molecular docking based three dimensional quantitative structure and activity relationship and molecular dynamics simulation studies have been carried out on indole derivatives reported as pim-1 inhibitors. Initially docking was carried out to obtain the receptor specific orientation of the molecules and later to understand the structural requirements of pim-1 inhibitors robust 3 D QSAR models were built using CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) methods. The reliability of the models was established from conventional (r) and cross validated (q) values of 0.982, 0.524 for CoMFA and 0.974, 0.586 for CoMSIA respectively. Further the predictive ability of the model was evaluated using a test set of 17 molecules. The docking studies revealed that interaction with Glu 121 is vital for binding of inhibitors to pim-1. Based on the outcome of the results new molecules with improved activity were designed. Furthermore, MD simulations were also performed to examine the stability of interactions and investigate the pivotal role of Glu 121.
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http://dx.doi.org/10.1080/10799893.2020.1713809DOI Listing
February 2020

Computational design, synthesis and evaluation of new sulphonamide derivatives targeting HIV-1 gp120.

J Comput Aided Mol Des 2020 01 2;34(1):39-54. Epub 2019 Dec 2.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500 007, India.

Attachment of envelope glycoprotein gp120 to the host cell receptor CD4 is the first step during the human immunodeficiency virus-1 (HIV-1) entry into the host cells that makes it a promising target for drug design. To elucidate the crucial three dimensional (3D) structural features of reported HIV-1 gp120 CD4 binding inhibitors, 3D pharmacophores were generated and receptor based approach was employed to quantify these structural features. A four-partial least square factor model with good statistics and predictive ability was generated for the dataset of 100 molecules. To further ascertain the structural requirement for gp120-CD4 binding inhibition, molecular interaction studies of inhibitors with gp120 was carried out by performing molecular docking using Glide 5.6. Based on these studies, structural requirements were drawn and new molecules were designed accordingly to yield new sulphonamides derivatives. A water based green synthetic approach was adopted to obtain these compounds which were evaluated for their HIV-1 gp120 CD4 binding inhibition. The newly synthesized compounds exhibited remarkable activity (10-fold increase) when compared with the standard BMS 806. Further the stability of newly synthesized derivatives with HIV-1 gp120 was also investigated through molecular dynamics simulation studies. This provides a proof of concept for molecular modeling based design of new inhibitors for inhibition of HIV-1 gp120 CD4 interaction.
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http://dx.doi.org/10.1007/s10822-019-00258-0DOI Listing
January 2020

Computational studies on N-phenyl pyrrole derivatives as MmpL3 inhibitors in Mycobacterium tuberculosis.

Comput Biol Chem 2019 Feb 19;78:81-94. Epub 2018 Nov 19.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad, 500 007, Telangana, India. Electronic address:

The fight against tuberculosis (TB) is a time immemorial one and the emergence of new drug resistant strains of Mycobacterium tuberculosis keeps throwing new challenges to the scientific community immersed in finding mechanisms to control this dreaded disease. Computer aided drug designing (CADD) is one of the several approaches that can assist in identifying the potent actives against Mycobacterium. In this work, a series of 109 known Mycobacterial membrane proteins large 3 (MmpL3) inhibitors were pooled and atom based 3D QSAR analysis was performed to understand the structural features essential for inhibitory activity against the MmpL3, known to be a key player in transporting substances critical for cell wall integrity of Mycobacterium. The data set employed was randomly split into training set and test set molecules. The training set of 74 molecules was used to derive CoMFA and CoMSIA models that were statistically reliable (CoMFA: q = 0.53; r = 0.93 and CoMSIA: q = 0.60; r = 0.93). The derived models also exhibited good external predictive ability (CoMFA: r = 0.78 and CoMSIA: r = 0.79). The results are quite encouraging and information derived from these analyses was applied to design new molecules. The designed molecule showed appreciable predicted activity values and reasonably good ADMET profile. The strategy used in designing new molecules can be pursued in the hunt for new chemical entities targeting MmpL3, expanding the existing arsenal against TB.
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http://dx.doi.org/10.1016/j.compbiolchem.2018.11.007DOI Listing
February 2019

One-pot synthesis, biological evaluation and molecular docking studies of fused thiazolo[2,3-b]pyrimidinone-pyrazolylcoumarin hybrids.

Mol Divers 2018 Nov 2;22(4):943-956. Epub 2018 Jul 2.

Department of Chemistry, National Institute of Technology, Warangal, Telangana State, 506004, India.

As a part of our endeavor toward the synthesis of a new class of biologically potent heterocyclic hybrids, a series of newly fused thiazolo[2,3-b]pyrimidinones bearing a pyrazolylcoumarin moiety (6a-p) were synthesized in acceptable yields. Anticipated structures of all titled compounds were in agreement with spectral and analytical (C, H and N) analyses. The compounds were screened for in vitro antibacterial activity against both G and G bacterial strains and antiproliferative activity against K562 (chronic myelogenous leukemia), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), COLO 205 (colorectal adenocarcinoma), HepG2 (hepatocellular carcinoma) cell lines. Further, potent antibacterial compounds were subjected to molecular docking studies in order to gain insight into their plausible binding modes and mechanism of action against MurB. The modeling results were in agreement with the experimental data.
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http://dx.doi.org/10.1007/s11030-018-9845-0DOI Listing
November 2018

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

Comput Biol Chem 2018 Apr 20;73:95-104. Epub 2017 Dec 20.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India. Electronic address:

Staphylococcus aureus is a gram positive bacterium. It is the leading cause of skin and respiratory infections, osteomyelitis, Ritter's disease, endocarditis, and bacteraemia in the developed world. We employed combined studies of 3D QSAR, molecular docking which are validated by molecular dynamics simulations and in silico ADME prediction have been performed on Isothiazoloquinolones inhibitors against methicillin resistance Staphylococcus aureus. Three-dimensional quantitative structure-activity relationship (3D-QSAR) study was applied using comparative molecular field analysis (CoMFA) with Q of 0.578, R of 0.988, and comparative molecular similarity indices analysis (CoMSIA) with Q of 0.554, R of 0.975. The predictive ability of these model was determined using a test set of molecules that gave acceptable predictive correlation (r Pred) values 0.55 and 0.57 of CoMFA and CoMSIA respectively. Docking, simulations were employed to position the inhibitors into protein active site to find out the most probable binding mode and most reliable conformations. Developed models and Docking methods provide guidance to design molecules with enhanced activity.
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http://dx.doi.org/10.1016/j.compbiolchem.2017.12.007DOI Listing
April 2018

Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors.

J Thorac Oncol 2018 05 31;13(5):721-726. Epub 2018 Jan 31.

Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology, Osmania University, Hyderabad, India. Electronic address:

Introduction: A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance.

Methods: A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant.

Results: The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward first- and next-generation kinase inhibitors.

Conclusions: The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies.
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http://dx.doi.org/10.1016/j.jtho.2018.01.003DOI Listing
May 2018

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

J Recept Signal Transduct Res 2018 Feb;38(1):61-70

a Department of Chemistry , University College of Science, Osmania University , Hyderabad , India.

Filamentous temperature-sensitive protein Z (FtsZ) is a protein encoded by the FtsZ gene that assembles into a Z-ring at the future site of the septum of bacterial cell division. Structurally, FtsZ is a homolog of eukaryotic tubulin but has low sequence similarity; this makes it possible to obtain FtsZ inhibitors without affecting the eukaryotic cell division. Computational studies were performed on a series of substituted 3-arylalkoxybenzamide derivatives reported as inhibitors of FtsZ activity in Staphylococcus aureus. Quantitative structure-activity relationship models (QSAR) models generated showed good statistical reliability, which is evident from r and r values. The predictive ability of these models was determined and an acceptable predictive correlation (r) values were obtained. Finally, we performed molecular dynamics simulations in order to examine the stability of protein-ligand interactions. This facilitated us to compare free binding energies of cocrystal ligand and newly designed molecule B1. The good concordance between the docking results and comparative molecular field analysis (CoMFA)/comparative molecular similarity indices analysis (CoMSIA) contour maps afforded obliging clues for the rational modification of molecules to design more potent FtsZ inhibitors.
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http://dx.doi.org/10.1080/10799893.2018.1426607DOI Listing
February 2018

Synthesis, anti-microbial activity, cytotoxicity of some novel substituted (5-(3-(1H-benzo[d]imidazol-2-yl)-4-hydroxybenzyl)benzofuran-2-yl)(phenyl)methanone analogs.

Chem Cent J 2018 Jan 9;12(1). Epub 2018 Jan 9.

Molecular Modelling and Medicinal Chemistry Group, Department of Chemistry, Osmania University, Hyderabad, Telangana, India.

Background: There is a dire need for the discovery and development of new antimicrobial agents after several experiments for a better resistance of microorganisms towards antimicrobial agents become a serious health problem for a few years in the past. As benzimidazole possess various types of biological activities, it has been synthesized, in the present study, a new series of (5-(3-(1H-benzo[d]imidazol-2-yl)-4-hydroxybenzyl)benzofuran-2-yl)(phenyl)methanone analogs by using the condensation and screened for its in vitro antimicrobial activity and cytotoxicity.

Results: The synthesized (5-(3-(1H-benzo[d]imidazol-2-yl)-4-hydroxybenzyl) benzofuran-2-yl)(phenyl)methanone analogs were confirmed by IR, H and C-NMR, MS spectra and HRMS spectral data. The synthesized compounds were evaluated for their in vitro antimicrobial potential against Gram-positive (Bacillus subtilis, Bacillus megaterium, Staph aureus and Streptococcus pyogenes), Gram-negative (Escherichia coli, Proteus vulgaris, Proteus mirabilis and Enterobacter aerogenes) bacterial and fungal (Aspergillus niger, Candida albicans, Fusarium oxysporum, Fusarium solani) strains by disc diffusion method and the minimum inhibitory concentration (MIC) in which it has been recorded in microgram per milliliter in comparison to the reference drugs, ciprofloxacin (antibacterial) and nystatin (antifungal). Further, the cytotoxicity (IC value) has also been assessed on human cervical (HeLa), Supt1 cancer cell lines by using MTT assay.

Conclusions: The following screened compounds (4d), (4f), (4g), (4k), (4l), (4o) and (4u) were found to be the best active against all the tested bacterial and fungal strains among all the demonstrated compounds of biological study. The MIC determination was also carried out against bacteria and fungi, the compounds (4f) and (4u) are found to be exhibited excellent potent against bacteria and fungi respectively. The compounds (4f) and (4u) were shown non-toxic in nature after screened for cytotoxicity against the cancer cell lines of human cervical (HeLa) and Supt1. Additionally, structure and antibacterial activity relationship were also further supported by in silico molecular docking studies of the active compounds against DNA topoisomerase.
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http://dx.doi.org/10.1186/s13065-017-0364-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760494PMC
January 2018

Molecular docking, 3D-QSAR, molecular dynamics, synthesis and anticancer activity of tyrosine kinase 2 (TYK 2) inhibitors.

J Recept Signal Transduct Res 2018 Oct - Dec;38(5-6):462-474

a Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry , University College of Science, Osmania University , Hyderabad , Telangana State , India.

A therapeutic rationale is proposed by selectively targeting tyrosine kinase 2 (TYK 2) to obtain potent TYK 2 inhibitors by molecular modeling studies. In the present study, we have taken tyrosine kinase (TYK 2) inhibitors and carried out molecular docking, 3 D quantitative structure-activity relationship (3D-QSAR) analysis and molecular dynamics (MD). Based on the 3D-QSAR results thirteen new compounds (R-1 to R-13) were designed and synthesized in good yields. The synthesized molecules were evaluated for their in vitro anticancer activity against LnCap and A549 cell lines. The molecules R-1, R-3, R-5, R-7, and R-10 exhibited considerable anti cancer activity.
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http://dx.doi.org/10.1080/10799893.2019.1585453DOI Listing
September 2019

Bis-spirochromanones as potent inhibitors of Mycobacterium tuberculosis: synthesis and biological evaluation.

Mol Divers 2017 Nov 24;21(4):999-1010. Epub 2017 Aug 24.

X-ray Crystallography Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, Telangana State, 500 007, India.

On the basis of reported antimycobacterial property of chroman-4-one pharmacophore, a series of chemically modified bis-spirochromanones were synthesized starting from 2-hydroxyacetophenone and 1,4-dioxaspiro[4.5] decan-8-one using a Kabbe condensation approach. The synthesized bis-spirochromanones were established based on their spectral data and X-ray crystal structure of 6e. All synthesized compounds were evaluated against Mycobacterium tuberculosis H37Rv (ATCC 27294) strain, finding that some products exhibited good antimycobacterial activity with minimum inhibitory concentration as low as [Formula: see text]. Docking studies were carried out to identify the binding interactions of compounds II, 6a and 6n with FtsZ. Compounds exhibiting good in vitro potency in the MTB MIC assay were further evaluated for toxicity using the HEK cell line.
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http://dx.doi.org/10.1007/s11030-017-9779-yDOI Listing
November 2017

Synthesis of -butyl (substituted benzamido)phenylcarbamate derivatives: anti-inflammatory activity and docking studies.

J Chem Biol 2017 Jul 5;10(3):105-115. Epub 2017 Apr 5.

Department of Biochemistry, University College of Science, Osmania University, Hyderabad, Telangana 500007 India.

A series of new -butyl 2-(substituted benzamido) phenylcarbamate - were synthesized by the condensation of -butyl 2-amino phenylcarbamate () with various substituted carboxylic acid in the presence of EDCI and HOBt as coupling reagent, obtain in excellent yields. The structures of all newly synthesized compounds were characterized spectroscopically and evaluated for in vivo anti-inflammatory activity compared to the standard drug, indomethacin, by using the carrageenan-induced rat paw edema protocol. Most of the compounds exhibited a promising anti-inflammatory activity within 9 to 12 h, the percentage of inhibition values ranging from 54.239 to 39.021%. The results revealed that the compounds and exhibited better or equivalent anti-inflammatory activity with the percentage of inhibition of 54.239 and 54.130%, respectively, which was comparable to standard drug. In addition to experimental results, in silico docking studies was used as a tool to verify and expand the experimental outcomes.
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http://dx.doi.org/10.1007/s12154-017-0168-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480262PMC
July 2017

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

J Recept Signal Transduct Res 2017 Oct 24;37(5):453-469. Epub 2017 May 24.

a Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry , University College of Science, Osmania University , Hyderabad , India.

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 and q values. The predictive ability of these models was determined using a test set of 25 molecules that gave acceptable predictive correlation (r) 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.
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http://dx.doi.org/10.1080/10799893.2017.1328442DOI Listing
October 2017

Computational analysis of ABL kinase mutations allows predicting drug sensitivity against selective kinase inhibitors.

Tumour Biol 2017 May;39(5):1010428317701643

1 Molecular Medicine and Therapeutics Laboratory, Centre for Plant Molecular Biology (CPMB), Osmania University, Hyderabad, India.

The ABL kinase inhibitor imatinib has been used as front-line therapy for Philadelphia-positive chronic myeloid leukemia. However, a significant proportion of imatinib-treated patients relapse due to occurrence of mutations in the ABL kinase domain. Although inhibitor sensitivity for a set of mutations was reported, the role of less frequent ABL kinase mutations in drug sensitivity/resistance is not known. Moreover, recent reports indicate distinct resistance profiles for second-generation ABL inhibitors. We thus employed a computational approach to predict drug sensitivity of 234 point mutations that were reported in chronic myeloid leukemia patients. Initial validation analysis of our approach using a panel of previously studied frequent mutations indicated that the computational data generated in this study correlated well with the published experimental/clinical data. In addition, we present drug sensitivity profiles for remaining point mutations by computational docking analysis using imatinib as well as next generation ABL inhibitors nilotinib, dasatinib, bosutinib, axitinib, and ponatinib. Our results indicate distinct drug sensitivity profiles for ABL mutants toward kinase inhibitors. In addition, drug sensitivity profiles of a set of compound mutations in ABL kinase were also presented in this study. Thus, our large scale computational study provides comprehensive sensitivity/resistance profiles of ABL mutations toward specific kinase inhibitors.
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http://dx.doi.org/10.1177/1010428317701643DOI Listing
May 2017

A novel piperazine linked β-amino alcohols bearing a benzosuberone scaffolds as anti-proliferative agents.

Bioorg Med Chem Lett 2017 02 13;27(4):792-796. Epub 2017 Jan 13.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Osmania University, Tarnaka, Hyderabad 500007, India.

A new series of 1-((9-chloro-2,3-dimethyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methoxy)-3-(4-phenylpiperzin-1-yl) propan-2-ols (6a-k) have been designed, synthesized and their structures were established by spectroscopic data (FT-IR, H NMR, C NMR, HRMS) and further confirmed by X-ray analysis. The newly synthesized compounds 6a-k were evaluated for their in vitro anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MDA-MB-231 (breast), A549 (lung) and MIAPACA (pancreatic). Among the compounds tested, the compound 6e displayed most potent activity against four cancer cell lines with GI values ranging from 0.010 to 0.097μM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against Colchicine binding site of β-tubulin.
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http://dx.doi.org/10.1016/j.bmcl.2017.01.031DOI Listing
February 2017

Integrating Multiple Receptor Conformation Docking and Multi Dimensional QSAR for Enhancing Accuracy of Binding Affinity Prediction.

Curr Comput Aided Drug Des 2017 ;13(2):127-142

Department of Chemistry, Molecular Modeling and Medicinal Chemistry Group, University College of Science, Osmania University, Hyderabad - 500007, India.

Background: The accuracy of molecular conformation for Quantitative Structure Activity Relationship (QSAR) studies is an important criteria, and the most favourable bioactive conformer selection is a tough task. Correct ligand alignment as input for 3D-QSAR is an important step that is prone to human biases. Multiple-dimensional QSAR (mQSAR) approach provides a promising alternative to classic 3D-QSAR for drug discovery purposes.

Objective: Obtaining ligand conformations from multiple receptor conformation docking (MRCD) will reduce the margin of error by incorporating the receptor based alignment of ligand conformations. To validate this assumption we performed 6D QSAR studies on reported HIV-1 protease inhibitors using Quasar 6.0.

Materials & Method: The ensemble of conformation was obtained by MRCD of ligands in thirteen crystal structures of HIV-1 protease. 6D QSAR model was built using 65 cyclic urea molecules reported as HIV-1 protease inhibitors. Predictive ability of the model was validated using 35 cyclic urea molecules as test set. External predictive ability of the model was evaluated using a set of 24 HIV-1 protease inhibitors having varied structural scaffold.

Result: 6D QSAR model obtained showed a reliable cross-validated r2(q2) of 0.899, r2(classic) of 0.908 and yielded a predictive r2 (p2) of 0.527. The ratio of q2/r2 was 0.991 and p2/q2 was 0.586 for external test set.

Conclusion: The QSAR results invariably suggest that our approach is suitable for the identification of molecules having HIV-1 protease inhibitory potency. The underlying philosophy combines flexible docking for the identification of the binding modes and 6D QSAR for their quantification.
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http://dx.doi.org/10.2174/1573409913666170119115841DOI Listing
October 2018

Synthesis, Spectral Characterization, DNA/ Protein Binding, DNA Cleavage, Cytotoxicity, Antioxidative and Molecular Docking Studies of Cu(II)Complexes Containing Schiff Base-bpy/Phen Ligands.

J Fluoresc 2017 May 17;27(3):953-965. Epub 2017 Jan 17.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, University College of Science, Osmania University, Hyderabad, 500007, India.

Ternary Cu(II) complexes [Cu(II)(L)(bpy)Cl] 1, [Cu(II)(L)(Phen)Cl] 2 [L = 2,3-dimethyl-1-phenyl-4(2 hydroxy-5-methyl benzylideneamino)-pyrazol-5-one, bpy = 2,2 bipyridine, phen =1,10 phenanthroline) were synthesized and characterized by elemental analyses, UV-Visible, FT-IR, ESR, Mass, thermogravimetric and SEM EDAX techniques. The complexes exhibit octahedral geometry. The interaction of the Cu(II) with cailf thymus DNA (CT-DNA) was explored by using absorption and fluorescence spectroscopic methods. The results revealed that the complexes have an affinity constant for DNA in the order of 10 M and mode of interaction is intercalative mode. The DNA cleavage study showed that the complexes cleaved DNA without any external agent. The interaction of Cu(II) complexes with bovine serum albumin (BSA) was also studied using absorption and fluorescence techniques. The cytotoxic activity of the Cu(II) complexes was probed in HeLa (human breast adenocarcinoma cell line), B16F10 (Murine melanoma cell line) and HEPA1-6 celllines, complex 1 has good cytotoxic activity which is comparable with the doxarubicin drug, with IC values ranging from 3 to 12.6 μM. A further molecular docking technique was employed to understand the binding of the complexes towards the molecular target DNA. Investigation of the antioxidative properties showed that the metal complexes have significant radical scavenging activity potency against DPPH radical.
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http://dx.doi.org/10.1007/s10895-017-2030-5DOI Listing
May 2017

Molecular dynamics and MM/GBSA-integrated protocol probing the correlation between biological activities and binding free energies of HIV-1 TAR RNA inhibitors.

J Biomol Struct Dyn 2018 02 1;36(2):486-503. Epub 2017 Feb 1.

a Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry , University College of Science, Osmania University , Hyderabad 500 007 , Telangana , India.

The interaction of HIV-1 transactivator protein Tat with its cognate transactivation response (TAR) RNA has emerged as a promising target for developing antiviral compounds and treating HIV infection, since it is a crucial step for efficient transcription and replication. In the present study, molecular dynamics (MD) simulations and MM/GBSA calculations have been performed on a series of neamine derivatives in order to estimate appropriate MD simulation time for acceptable correlation between ΔG and experimental pIC values. Initially, all inhibitors were docked into the active site of HIV-1 TAR RNA. Later to explore various conformations and examine the docking results, MD simulations were carried out. Finally, binding free energies were calculated using MM/GBSA method and were correlated with experimental pIC values at different time scales (0-1 to 0-10 ns). From this study, it is clear that in case of neamine derivatives as simulation time increased the correlation between binding free energy and experimental pIC values increased correspondingly. Therefore, the binding energies which can be interpreted at longer simulation times can be used to predict the bioactivity of new neamine derivatives. Moreover, in this work, we have identified some plausible critical nucleotide interactions with neamine derivatives that are responsible for potent inhibitory activity. Furthermore, we also provide some insights into a new class of oxadiazole-based back bone cyclic peptides designed by incorporating the structural features of neamine derivatives. On the whole, this approach can provide a valuable guidance for designing new potent inhibitors and modify the existing compounds targeting HIV-1 TAR RNA.
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http://dx.doi.org/10.1080/07391102.2017.1281762DOI Listing
February 2018

Design, synthesis, molecular-docking and antimycobacterial evaluation of some novel 1,2,3-triazolyl xanthenones.

Medchemcomm 2017 Mar 3;8(3):559-570. Epub 2017 Jan 3.

Molecular Modeling and Medicinal Chemistry Group , Department of Chemistry , Osmania University , Hyderabad , Telangana-500 007 , India.

As part of an ongoing effort to develop new antitubercular and antimicrobial agents, a series of substituted xanthenone derivatives () were synthesized. Xanthenone derivatives () were prepared a one-pot three-component thermal cyclization reaction of β-naphthol (), substituted 1-aryl-1-[1,2,3]triazole-4-carbaldehydes (), and cyclic-1,3-diones (, ) in the presence of a catalytic amount of iodine. The newly synthesized compounds were characterized by IR, NMR, mass spectral data, and elemental analysis. These compounds ( and ) were screened for antitubercular activity against the HRv (ATCC 27294) strain, for antibacterial activity against Gram-positive and Gram-negative strains, and for antifungal activity against a pathogenic strain of fungi. Among the compounds tested, most of them showed good to excellent antimicrobial and antitubercular activity. The active compounds displaying good potency in the MTB were further examined for toxicity in a HEK cell line. In addition, the structure and antitubercular activity relationship were further supported by molecular-docking studies of the active compounds against the pantothenate synthetase (PS) enzyme of .
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http://dx.doi.org/10.1039/c6md00593dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072411PMC
March 2017

Synthesis and evaluation of naphthyl bearing 1,2,3-triazole analogs as antiplasmodial agents, cytotoxicity and docking studies.

Bioorg Med Chem 2017 01 25;25(1):221-232. Epub 2016 Oct 25.

Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad 500007, Telangana, India.

Novel series of naphthyl bearing 1,2,3-triazoles (4a-t) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j, 4k, 4l, 4m, 4n, 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m, 4n and 4t (∼3.0-fold) displayed superior activity to Pyr against resistant strain. Pyr and selected compounds (4n, 4p and 4t) that repressed parasite development also inhibited PfDHFR activity of the soluble parasite extract, suggesting that anti-parasitic activity of these compounds is a result of inhibition of the parasite DHFR. In silico studies suggest that activity of these compounds might be enhanced due to π-π stacking.
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http://dx.doi.org/10.1016/j.bmc.2016.10.029DOI Listing
January 2017

Design, synthesis and docking studies of novel 1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamide derivatives as a potential anti-proliferative agents.

Eur J Med Chem 2017 Jan 21;125:400-410. Epub 2016 Sep 21.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Osmania University, Tarnaka, Hyderabad, 500007, India.

A new series of 4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide hybrids 8a-l have been designed and synthesized using peptide coupling agents with substituted N-phenyl piperazines and piperidines with good to excellent yields. The synthesized compounds were evaluated for their in vitro anti-proliferative activity against PANC 1, HeLa and MDA-MB-231. The compounds 8d, 8e, 8f, 8g, 8h and 8k exhibited considerable anti-proliferative activity with GI values ranging from 0.15 to 1.4 μM. The structure and anti-proliferative activity relationship was further supported by in silico molecular docking study of the active compounds against tubulin protein.
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http://dx.doi.org/10.1016/j.ejmech.2016.09.062DOI Listing
January 2017

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

Comput Biol Chem 2016 10 17;64:33-46. Epub 2016 May 17.

Department of Chemistry, University College of Science, Osmania University, Hyderabad 07, India. Electronic address:

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 and r values. The predictive ability of this model was determined using a test set of 13 molecules that gave acceptable predictive correlation (r) 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.
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http://dx.doi.org/10.1016/j.compbiolchem.2016.04.009DOI Listing
October 2016

Quinazolinones-Phenylquinoxaline hybrids with unsaturation/saturation linkers as novel anti-proliferative agents.

Bioorg Med Chem Lett 2016 07 11;26(13):3014-3018. Epub 2016 May 11.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Osmania University, Tarnaka, Hyderabad 500007, India.

A new series of novel quinazolinones with allylphenyl quinoxaline hybrids 9a-n were efficiently synthesized in good yields by the reaction of 3-allyl-2-methylquinazolin-4(3H)-one (5a-n) with bromophenyl)quinoxaline (8) utilizing Pd catalyzed Heck-cross coupling and evaluated for anti-proliferative activity against four cancer cell lines such as HeLa (cervical), MIAPACA (pancreatic), MDA-MB-231 (breast) and IMR32 (neuroblastoma). Compounds 9a, 9e, 9g and 9h exhibited promising anti-proliferative activity with GI50 values ranging from 0.06 to 0.2μM against four cell lines, while compounds 9e and 9k showed significant activity against HeLa and MIAPACA cell lines and compounds 9b, 9d, 9h and 9j showed selective potency against IMR32 and MDA-MB-231 cell lines. This is the first report on the synthesis and in vitro anti-proliferative evaluation of E-2-(4-substituted)-3-(3-(4-(quinoxalin-2-yl)phenyl)allyl)quinazolin-4(3H)-ones (9a-n). Docking results indicate a sign of good correlation between experimental activity and calculated binding affinity (dock score), suggesting that these compounds could act as promising DNA intercalates.
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http://dx.doi.org/10.1016/j.bmcl.2016.05.021DOI Listing
July 2016

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

J Recept Signal Transduct Res 2016 Oct 12;36(5):488-504. Epub 2016 Jan 12.

a Department of Chemistry , University College of Science, Osmania University , Hyderabad , India and.

Anaplastic lymphoma kinase (ALK), a promising therapeutic target for treatment of human cancers, is a receptor tyrosine kinase that instigates the activation of several signal transduction pathways. In the present study, in silico methods have been employed in order to explore the structural features and functionalities of a series of tetracyclic derivatives displaying potent inhibitory activity toward ALK. Initially docking was performed using GLIDE 5.6 to probe the bioactive conformation of all the compounds and to understand the binding modes of inhibitors. The docking results revealed that ligand interaction with Met 1199 plays a crucial role in binding of inhibitors to ALK. Further to establish a robust 3D-QSAR model using CoMFA and CoMSIA methods, the whole dataset was divided into three splits. Model obtained from Split 3 showed high accuracy ([Formula: see text] of 0.700 and 0.682, [Formula: see text] of 0.971 and 0.974, [Formula: see text] of 0.673 and 0.811, respectively for CoMFA and CoMSIA). The key structural requirements for enhancing the inhibitory activity were derived from CoMFA and CoMSIA contours in combination with site map analysis. Substituting small electronegative groups at Position 8 by replacing either morpholine or piperidine rings and maintaining hydrophobic character at Position 9 in tetracyclic derivatives can enhance the inhibitory potential. Finally, we performed molecular dynamics simulations in order to investigate the stability of protein ligand interactions and MM/GBSA calculations to compare binding free energies of co-crystal ligand and newly designed molecule N1. Based on the coherence of outcome of various molecular modeling studies, a set of 11 new molecules having potential predicted inhibitory activity were designed.
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http://dx.doi.org/10.3109/10799893.2015.1130057DOI Listing
October 2016

Synthesis, antimicrobial activity and molecular docking of novel tetracyclic scaffolds incorporating a flavonoid framework with medium sized oxygen heterocycles.

Bioorg Med Chem Lett 2015 Feb 30;25(4):898-903. Epub 2014 Dec 30.

Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.

A convenient approach for the synthesis of novel tetracyclic scaffolds incorporating a flavonoid framework with medium sized heterocyclic rings (eight-, nine-, ten- and eleven-membered rings) containing two oxygen atoms from flavonols through alkylation using different dibromoalkanes was described. The synthesized compounds were established based on the spectral data and X-ray crystal structure for 6c. The synthesized compounds were evaluated for their in vitro antimicrobial activity. Docking studies were carried out for most active two compounds 6f and 6i.
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http://dx.doi.org/10.1016/j.bmcl.2014.12.066DOI Listing
February 2015

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

J Recept Signal Transduct Res 2014 Oct 21;34(5):417-30. Epub 2014 Jul 21.

Department of Chemistry, University College of Science, Osmania University , Hyderabad, Andhra Pradesh , India.

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.
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http://dx.doi.org/10.3109/10799893.2014.917323DOI Listing
October 2014

Induced fit docking, pharmacophore modeling, and molecular dynamic simulations on thiazolidinedione derivatives to explore key interactions with Tyr48 in polyol pathway.

J Mol Model 2014 Jul 29;20(7):2348. Epub 2014 Jun 29.

Molecular Modeling and Medicinal Chemistry Group, Dept. of Chemistry, University College of Science, Osmania University, Hyderabad, 500-007, India,

To obtain a scientific thought and expedition to explore key interactions with Tyr48 in aldose reductase (ALR), combined study of pharmacophore modeling, induced fit docking, and dynamics studies were performed on ALR. A stereo chemically and energetically valid model of ALR-NADP+ complex was developed using homology modeling technique. Statistically a significant five point pharmacophore model was designed on a set of 54 thiazolidinedione derivatives with good external and internal predictive ability. Rigid and induced fit docking protocols were applied on ALR protein for both with and without NADP+ cofactor to identify a suitable binding mode that facilitates the key hydrogen bond interactions with Tyr48. Docking of thiazolidinedione derivatives into ALR-NADP+ complex gave more promising results by reducing false positive binding of inhibitors into the co-factor binding site. Structural changes within Try48 and Asp43 during the binding process in enzyme inhibitor complex were analyzed using molecular dynamics (MD) simulations. The results obtained from dynamic simulations emphasized the role of Tyr48 in maintaining inter or intra molecular hydrogen bond interaction with the protein or inhibitor respectively. New molecules were designed and checked for their binding interactions and showed improved results compared to existing thiazolidinediones derivatives. Hence, these combined protocols will be helpful and cooperative to design and optimize molecules with better inhibitory activity against the biologically active target.
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http://dx.doi.org/10.1007/s00894-014-2348-8DOI Listing
July 2014

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

J Recept Signal Transduct Res 2014 Jun 23;34(3):185-94. Epub 2014 Jan 23.

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Nizam College, Osmania University , Basheerbagh, Hyderabad , India.

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.
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http://dx.doi.org/10.3109/10799893.2013.869601DOI Listing
June 2014
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