Abstract
Motivation: Leishmania infantum is the primary cause of VL, and its trypanothione reductase (TR) creates a favorable environment in the host, making TR an attractive drug target. This study aims to identify potential TR inhibitors from Azadirachta indica phytochemicals using molecular modeling techniques. Results: Sixty compounds from A. indica were screened via molecular docking for their binding affinity to TR, followed by binding free energy calculations. Drug-likeness, pharmacokinetics, and toxicity properties of the hit compounds were then evaluated. The top compounds were subjected to a 100 ns molecular dynamics (MDs) simulation to further assess the stability of their interaction with TR. Ten of the screened compounds exhibited higher affinity for TR compared to miltefosine (standard drug), with docking scores ranging from -3.501 to -8.482 kcal/mol, compared to miltefosine's -3.231 kcal/mol. All the drug-like hit compounds showed favorable pharmacokinetics and toxicity profiles and their binding free energies indicated stable interactions. MDs simulations confirmed that these interactions persisted for most of the simulation time, confirming the stability and potential efficacy of the compounds as TR inhibitors. Availability and Implementation: This study identifies isorhamnetin, meliantriol, and quercetin as promising candidates for further in vitro and in vivo evaluation for the development of TR inhibitors against L. infantum.