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

<i>Brugia malayi</i>, a causative agent of lymphatic filariasis, relies on its endosymbiont <i>Wolbachia</i> for survival. MurE ligase, a key enzyme in <i>Wolbachia</i> 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 <i>Wolbachia</i> endosymbiont of <i>B. malayi</i> (<i>wBm</i>MurE). A validated high-quality model of <i>wBm</i>MurE 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 <i>N</i>-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 <i>wBm</i>MurE. These findings suggest that selected phytochemicals could serve as starting points for the development of novel anti-filarial agents.