Targeting spermidine synthase in Leishmania donovani: molecular docking and molecular dynamics simulation-based...

Visceral leishmaniasis, caused by Leishmania donovani, remains a critical global health challenge due to limited, toxic, and costly treatment options and rising drug resistance. Targeting spermidine synthase (LdSpdS), an essential enzyme for parasite growth, we explored plant-derived phytochemicals as potential inhibitors. A curated phytochemical-inhibitor library was screened against a homology-modeled LdSpdS structure using molecular docking, identifying anaferine, asparagamine A, and isozeylanone as top candidates with strong binding affinities. Drug-likeness evaluation supported their favorable physicochemical properties. Toxicity profiling revealed asparagamine A as the safest candidate, whereas anaferine and isozeylanone exhibited neurotoxic, immunotoxic, and genotoxic liabilities, emphasizing the need for experimental validation. Molecular dynamics simulations and g-MMPBSA binding energy analyses confirmed the conformational stability and robust interactions of the LdSpdS-ligand complexes. Collectively, these findings highlight anaferine, asparagamine A, and isozeylanone as promising lead molecules for LdSpdS-targeted antileishmanial therapy, providing a foundation for future pharmacological development and in vitro/in vivo evaluation.