MurC ligase of multi-drug resistant Salmonella Typhi can be inhibited by novel Curcumin derivative: Evidence from molecular docking and dynamics simulations.

Abstract

Emerging multi-drug resistance in recent Salmonella Typhi isolates, causative agent of enteric Typhoid fever, compelled us to investigate alternative therapeutic strategies. The present study encompassed virtual screening, ADMET screening as well as antibacterial activity prediction to shortlist potent lead molecules whose binding affinities (BAs) were checked against major druggable S. Typhi targets. BA profile revealed a deoxy-tetradeutero- curcumin derivative to be novel bioactive compound having high BA towards UDP-N-acetylmuramate-L-alanine ligase (MurC) protein involved in peptidoglycan synthesis. Molecular docking indicated that our lead {Binding energy (BE)=-8.00±0.02kcal/mol}could competitively bind to MurC with respect to its natural ligand ATP (BE= -7.65±0.19kcal/mol). The lead also possessed superior binding and inhibition profile against MurC than other commercial antibiotics. This BE was contributed by Hydrogen (H-) bonds and numerous non-canonical interactions with the evolutionary conserved active-site residues. From molecular docking and coarse-grained dynamics simulations, it was inferred that the novel curcumin derivative was predicted to be potential competitive inhibitor of ATP for MurC-catalytic domain having low relative RMSF (0.59Å) to inhibit MurC-induced peptidoglycan biosynthesis. The inferences drawn from the study can open new portals for designing efficient therapeutic strategies against S. Typhi.