Structural bioinformatics insights into UDP-galactopyranose mutase (UGM) as a novel drug target for antifilarial therapy against human filarial parasite Brugia malayi.

Abstract

A flavoenzyme, UDP-galactopyranose mutase (UGM), serves as a pivotal enzyme catalysing the conversion of UDP-galactopyranose (galP) into UDP-galactofuranose (galF), a metabolite exclusively present in pathogenic microorganisms, including filarial parasites. The galF plays a critical role in various pathogenic processes, like cell wall biosynthesis, virulence enhancement, and cuticle formation in filarial parasites. Notably, the absence of galF in humans renders, UGM an attractive and promising drug target for developing potent antifilarial therapeutics. In this study, we employed advanced bioinformatics approaches to identify effective antifilarial drug candidates. The UGM enzyme from Brugia malayi (BmUGM) was meticulously modelled and subsequently utilized for molecular docking studies against 20 triazolothiadiazine analogues using the AutoDock program. Among these, eight compounds exhibiting high binding affinities, ranging from - 8.7 to - 10.5 kcal/mol, were selected for further protein-ligand MD simulations. Post-simulation analyses, encompassing MM-PBSA and binding free energy decomposition, demonstrated that two triazolothiadiazine analogues, namely D4 and D8, exhibited exceptionally high binding free energies of - 29.76 kcal/mol and - 27.50 kcal/mol, respectively. These values exceeded the binding free energy of the natural substrate galP, which was calculated at - 20.01 kcal/mol. Furthermore, binding free energy decomposition analysis pinpointed critical binding site residues Tyr168, Trp184, Tyr326, Tyr335, Arg336, Tyr405, and Gln475 as essential mediators of the protein-ligand interactions. Additionally, ADMET and DFT quantum mechanical calculations confirmed that the triazolothiadiazine analogues exhibit low toxicity profiles and favourable chemical reactivity. Based on these findings, we propose that the identified ligand molecules hold potential as potent inhibitors of BmUGM, with broad-spectrum efficacy against all life stages of filarial parasites.