Insight into Inhibitory Activity of Mycobacterial Dihydrofolate Reductase Inhibitors by In-silico Molecular Modeling Approaches

To facilitate the discovery of Mycobacterium avium complex dihydrofolate reductase (MAC DHFR) inhibitors, various molecular modeling studies such as homology modeling, pharmacophore mapping, and 3D-QSAR studies were undertaken. To address the issue of bioactive conformer in ligand-based approaches, ensemble of conformers obtained from docking studies was used for pharmacophore mapping and for 3D-QSAR studies. The developed structure-chemical-feature-based pharmacophore model was consistent with the structure-functional requirements for the binding of the DHFR inhibitors. Using the generated homology model, interactions between the reported inhibitors were explored. The results showed that the type and spatial location of chemical features encoded in the pharmacophore and 3D-QSAR contours are in agreement with the enzyme inhibitor interaction pattern identified from molecular docking. The outcomes of the study could be used for the rational design of potent and selective MAC DHFR inhibitors.