A computational study of Di-substituted 1,2,3-triazole derivatives as potential drug candidates against Mycobacterium tuberculosis: 3D-QSAR, molecular docking, molecular dynamics, and ADMETox

Multidrug-resistant TB (MDR TB) strains have become a severe issue, motivating researchers to find new TB drugs effective against these MDR strains. In this work, 3D-QSAR (three-dimensional quantitative structure-activity relationship), molecular docking, ADMET, and molecular dynamics studies were performed to investigate the inhibitory activity of 1,2,3-triazole derivatives against Mycobacterium tuberculosis by acting as H37Rv active site inhibitors. The 3D-QSAR study was conducted based on molecular field comparative analysis (CoMFA) and molecular similarity index benchmarking (CoMSIA), which revealed CoMFA model values (Q(2) = 0.62; R-2 = 0.95) and CoMSIA model values (Q(2) = 0.57; R-2 = 0.84) for the best-observed models. These values presented excellent predictability, which was also evaluated by using the criteria established by A. Golbraikh and A. Tropsha. A molecular docking interaction between the Gln164 and Lys160 residues was observed at the mycobacterial active site H37Rv, as verified by the interaction type, total score, and MD molecular dynamics. Furthermore, the ADMET properties and drug similarity of these new inhibitors were analyzed. Our results can help researchers synthesize new therapeutic candidates against multidrug-resistant tuberculosis.

Automated summary

In this study, 3D-QSAR, molecular docking, ADMET, and molecular dynamics were used to investigate the inhibitory activity of 1,2,3-triazole derivatives against Mycobacterium tuberculosis. The 3D-QSAR study revealed CoMFA and CoMSIA models with good predictability. Molecular docking confirmed the interaction between Gln164 and Lys160 residues at the H37Rv active site. Furthermore, the ADMET properties and drug similarity of the new inhibitors were analyzed. These findings can aid in the development of new therapeutic candidates against multidrug-resistant tuberculosis.