Title:Possible Binding Mode Analysis of Pyrazolo-triazole Hybrids as Potential Anticancer Agents through Validated Molecular Docking and 3D-QSAR Modeling Approaches
VOLUME: 14 ISSUE: 5
Author(s):Siekh Abdul Amin, Nilanjan Adhikari, Ram K. Agrawal, Tarun Jha* and Shovanlal Gayen*
Affiliation:Department of Pharmaceutical Sciences, Laboratory of Drug Design and Discovery, Dr. Harisingh Gour University (A Central University), Sagar 470003, MP, Department of Pharmaceutical Technology, Natural Science Laboratory, Division of Medicinal and Pharmaceutical Chemistry, P.O. Box 17020, Jadavpur University, Kolkata 700032, WB, Department of Pharmaceutical Sciences, Laboratory of Drug Design and Discovery, Dr. Harisingh Gour University (A Central University), Sagar 470003, MP, Department of Pharmaceutical Technology, P.O. Box 17020, Jadavpur University, Kolkata, 700032, WB, Laboratory of Drug Design and Discovery, Department of Pharmaceutical Sciences, Dr. Harisingh Gour University (A Central University), Sagar 470003, MP
Keywords:ADMET, anticancer agents, druggability prediction, k-Nearest neighbor molecular field analysis, molecular
docking, pyrazolo-triazole hybrids.
Abstract:Background: There has been a growing interest of pharmacophore hybridization in
anticancer drug discovery that may be utilized for designing new potential lead candidates against
multiple targets that may exhibit synergetic activity. Pyrazole and 1,2,3-triazole nucleus are amongst the
most important ones.
Method: Statistically validated 3D-QSAR models of the pyrazolo-triazole hybrids on 4 different types
of human cancer cell lines (U87MG, PC-3, HT-29 and A549) are constructed through simulated
annealing k-Nearest neighbor molecular field analysis (SA-kNN-MFA) method followed by robust
molecular docking study, druggability assessment and in silico ADMET analysis.
Results: 3D-QSAR study reveales the importance of electronegative group at R1 position and 3, 4-
OCH3 substituent at R2 position that may enhance biological potency against these cancer cell lines. The
docking analysis suggests that the pyrazolo-triazole hybrids may have better binding affinities compared
to the redocked co-crystallized ligand for targets namely CDK-2, CDK-5, FTase, HSP-90, TGF-β,
topoisomerase-I and tubulin. Moreover, these compounds show better ADMET profile than the standard
drug 5-fluorouracil.
Conclusion: The results of molecular docking, druggability and ADMET analysis may focus the utility
of targeting these possible potential enzymes for developing newer pyrazolo-triazoles as multi-targeted
anticancer agents.
