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

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 R-1 position and 3,4-OCH3 substituent at R-2 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-beta, 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.