Disrupting tuberculosis pathogenesis by targeting DprE1 in cell wall biosynthesis: a structural dynamics perspective.

Mycobacterium tuberculosis (Mtb), the causative agent of TB, remains a major global health challenge due to the emergence of MDR and XDR strains. Targeting DprE1, an enzyme essential in the biosynthesis of the mycobacterial cell wall, offers a promising therapeutic strategy. The current work utilized a computational pipeline for identifying potential inhibitors of DprE1 from the Diverse-lib database by virtual screening, molecular docking, molecular dynamics, free binding energy calculation, and free energy landscape analysis based on RMSD and Rg values. Three candidates were identified as promising inhibitors out of all the screened diverse-lib compounds. Their binding poses and interaction patterns were analyzed and compared with those of a known reference inhibitor. In molecular docking, three compounds showed high binding affinities, while MD simulations further showed stable protein-ligand complexes for more than 300 nsec in quadruplicate. Free binding energy calculation through MM/GBSA revealed energetically favorable interactions. From this RMSD-Rg-based free energy landscape, the stability in conformation was indicated in the complexes. Minima structures also strongly agreed with initial poses, evidenced by superimposition analysis. Comparison with the reference molecule revealed that the identified compounds exhibit comparable or higher binding energies and structural stability, suggesting their potential to inhibit DprE1. These findings warrant further experimental validation to confirm their efficacy against Mtb.