Visceral Leishmaniasis: Integrated In Silico Screening of Djiboutian Medicinal Plant Phytoconstituents Targeting Leishmania donovani and Leishmania infantum

Abstract

Objectives: Visceral leishmaniasis (VL), caused by Leishmania donovani and Leishmania infantum, is a life-threatening neglected tropical disease, particularly in endemic regions such as Djibouti. Current therapies are constrained by toxicity, high cost, and limited availability, highlighting the urgent need for safe, effective, and affordable alternatives. This study aimed to identify novel antileishmanial candidates from Djiboutian medicinal plants using an integrated in silico approach. Methods: A total of 136 phytoconstituents isolated from local medicinal plants were screened via molecular docking against validated protein targets (6UAK and 2JK6). Promising candidates were further analyzed for interaction patterns, drug-likeness according to Lipinski’s Rule of Five, and ADMET properties. Molecular dynamics (MD) simulations over 100 ns were performed to assess the structural stability of selected protein–ligand complexes. Results: Compound C41 emerged as a leading candidate, showing binding affinities of −8.3 kcal/mol and −7.5 kcal/mol toward 6UAK and 2JK6, respectively, comparable to reference drugs. Interaction analysis revealed stable hydrogen bonds and hydrophobic contacts within the catalytic sites. Drug-likeness assessment confirmed compliance with Lipinski’s Rule, while ADMET predictions indicated high intestinal absorption and favorable safety profiles for several candidates. MD simulations corroborated the structural stability of the 2JK6-C41 complex throughout the 100 ns trajectory. Conclusions: These findings underscore Djiboutian medicinal plants as a valuable source of potential antileishmanial leads. Among them, Compound C41 represents a promising candidate for future experimental validation, supporting the development of innovative, safe, and cost-effective therapies against visceral leishmaniasis.