Possible Binding Mode Analysis of Pyrazolo-triazole Hybrids as Potential Anticancer Agents through Validated Molecular Docking and 3D-QSAR Modeling Approaches

Author(s): Siekh Abdul Amin, Nilanjan Adhikari, Ram K. Agrawal, Tarun Jha*, Shovanlal Gayen*.

Journal Name: Letters in Drug Design & Discovery

Volume 14 , Issue 5 , 2017

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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.

Keywords: ADMET, anticancer agents, druggability prediction, k-Nearest neighbor molecular field analysis, molecular docking, pyrazolo-triazole hybrids.

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Article Details

VOLUME: 14
ISSUE: 5
Year: 2017
Page: [515 - 527]
Pages: 13
DOI: 10.2174/1570180813666160916153017
Price: $65

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