Developing novel indoles as antitubercular agents and simulated-annealing based analysis of their binding with MmpL3

This research is an attempt to develop novel indole-2-carboxamides as antitubercular agents and understand their binding interactions at the catalytic site. In this study, mycobacterial membrane protein Large 3 (MmpL3) was chosen as the drug target and the indole-2-carboximides were designed, synthesized, and screened for antitubercular activity. Molecular modelling techniques for designing and validation included building a homology model, docking, and MMGBSA. A total of 12 molecules were synthesized and tested against the H37Rv strain of Mycobacterium tuberculosis among which three molecules exhibited MIC of less than 1 µM. Those compounds were also found to be active against different multidrug-resistant (MDR) and extensively drug resistant (XDR) strains of the bacteria and results from the iniBAC promoter induction study indicated that the potent molecules could be inhibitors of MmpL3. Finally, simulated annealing studies performed with a couple of active molecules led to a detailed understanding of the protein-ligand interactions at the MmpL3 binding pocket.