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

Abstract

Aim: This research aimed to develop novel indole-2-carboxamides as potential antitubercular agents using rational drug design. It also focused on identifying the critical interactions required for these compounds to exhibit effective antitubercular activity.

Materials and methods: Novel indole-2-carboxamides targeting MmpL3 were designed based on SAR, synthesized, and tested for their antitubercular and iniBAC induction properties. Classical docking and simulated annealing were utilized to understand protein-ligand binding affinity.

Results: Compounds 5c, 5f, and 5i, were active against H37Rv and different MDR and XDR strains of M. tuberculosis. iniBAC promoter induction study indicated that those were inhibitors of MmpL3. Through the docking and simulated annealing studies, we identified key protein-ligand interactions at the MmpL3 binding site.

Conclusion: We have identified three potent antitubercular molecules that supposedly act via inhibiting MmpL3. Results from the molecular modeling studies can be used in future drug designing.

Keywords: MmpL3; indole-2-carboxamides; molecular docking; simulated annealing; tuberculosis.

Figure 1.

Two different design strategy of new molecules shown in (a) and (b), where n refers to the number of carbons in the alkyl chain.

Figure 2.

Synthetic route of compounds 5a–5i.

Figure 3.

Synthetic route of compounds 7a–7c.

Figure 4.

(a) Protein–ligand contact summary of 5iT–MmpL3 complex. (b) Protein–-ligand contact histogram of 5iT–MmpL3 complex.

Figure 5.

(a) Protein–ligand contact summary of 5iC–MmpL3 complex. (b) Protein–ligand contact histogram of 5iC–MmpL3 complex.