Molecular docking of Berberis asiatica-derived compounds targeting DDX3 DEAD BOX RNA helicase of Leishmania donovani.

Visceral leishmaniasis (VL), caused by Leishmania donovani, continues to pose a significant global health burden, especially in tropical and subtropical regions. Current therapeutic options are limited by toxicity, high cost, and emerging drug resistance, necessitating the discovery of novel, safer alternatives. In this study, molecular docking approaches were used to identify potential inhibitors of LdHEL-67, a crucial DEAD-box RNA helicase (DDX3 family) in L. donovani. A total of 100 bioactive compounds were identified through GC-MS analysis of ethanol and hexane extracts of Berberis asiatica, of which 48 compounds were selected based on their percentage occurrence in extracts. These compounds were initially docked against LdHEL-67 and its human homolog (PDB ID: 6CZ5) using PyRx for comparative analysis. To enhance reliability, all 48 compounds were re-docked using AutoDock, and 14 compounds with the highest binding affinities were shortlisted for further evaluation. For example, Compound 21 exhibited binding energies of - 11.7 kcal/mol (AutoDock) and - 6.5 kcal/mol (PyRx), while Compound 47 showed - 11.4 kcal/mol and - 7.5 kcal/mol, respectively. Cavity detection using CavityPlus predicted one prominent druggable pocket each for LdHEL-67 and its human counterpart, into which the top 14 compounds were subsequently docked. Top 14 compounds analysed for ADMET and toxicity prediction. In-vitro assays using ethanol and hexane extracts demonstrated significant anti-promastigote activity against L. donovani with minimal cytotoxicity to THP-1-derived macrophages. These results highlight the therapeutic potential of B. asiatica-derived compounds and support further exploration of LdHEL-67 as a promising drug target for VL treatment. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00377-7.