Harnessing the potential of phytochemicals to design anti-filarial molecules targeting the MurE enzyme of Brugia malayi: a hierarchical virtual screening and molecular dynamics simulation study.

Abstract

Brugia malayi, a causative agent of lymphatic filariasis, relies on its endosymbiont Wolbachia for survival. MurE ligase, a key enzyme in Wolbachia peptidoglycan biosynthesis, serves as a promising drug target for anti-filarial therapy. In this study, we employed a hierarchical virtual screening pipeline to identify phytochemical inhibitors targeting the MurE enzyme of the Wolbachia endosymbiont of B. malayi (wBmMurE). A validated high-quality model of wBmMurE was used to screen 17,967 phytochemicals, and the identified hits were subjected to toxicity profiling, and ADME filters to select potent drug-like candidates. Five phytochemicals such as biotin, quisqualic acid, succinic acid, 9,14-dihydroxyoctadecanoic acid, and N-isovaleroylglycine with permissible ADME profiles showed favourable binding affinities (GlideScore range: -12.86 to -10.57 kcal/mol), and stable interactions with catalytically important residues were selected from screened hits. Comparative analysis with reported MurE inhibitors validated the superior affinity and drug-like behaviour of our identified leads. Molecular dynamics simulations of 300 ns confirmed the conformational stability of ligand-bound complexes, while MM-GBSA analysis supported their favourable binding free energies. The results revealed that the identified compounds have the tendency of binding within substrate binding cavity of wBmMurE. These findings suggest that selected phytochemicals could serve as starting points for the development of novel anti-filarial agents.