Skimmin as lead inhibitor of Leishmania donovani’s O-acetyltransferase: a computational study

Abstract

Leishmaniasis, a protozoan disease with significant global morbidity, manifests as Cutaneous, Mucocutaneous, and Visceral forms caused by Leishmania species. Visceral Leishmaniasis (VL), caused by Leishmania donovani, poses particular fatality due to its infiltration of the central nervous system (CNS). The emergence of multidrug resistance (MDR) in L. donovani underscores the need for alternative therapeutic strategies. Plant secondary metabolites, acting as inhibitors against L. donovani's survival pathways, present a promising avenue for drug development. The cysteine synthase pathway, crucial for L. donovani’s survival, can be targeted for inhibition, focusing on the O-acetyltransferase (OASS) enzyme. OASS, pivotal in this pathway and absent in humans, becomes an attractive drug target. Initiating with the selection and optimization of OASS's 3D structure (PDB Id-3TBH), virtual screening against a plant metabolite library identified lead compounds with high binding affinities. Four potential candidates were shortlisted based on estimated free energy of binding and drug likeliness. These candidates underwent molecular dynamics simulations, providing insights into protein–ligand interactions via structural analyses. Additionally, Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) analysis calculated binding free energies. Results indicated Skimmin (IMPHY007363) as a potential lead molecule for inhibiting OASS in Leishmania donovani, showing promise for further drug development against this devastating disease.

Graphical Abstract