Computational evaluation of phytochemicals targeting DNA topoisomerase I in : molecular docking and molecular dynamics simulation studies.

DNA topoisomerase I (Topo I) is a ubiquitous enzyme that plays a crucial role in resolving the topological constraints of supercoiled DNA during various cellular activities, including repair, replication, recombination, transcription, and chromatin remodeling. Multiple studies have confirmed the essential role of Topo I in nucleic acid metabolism of , the kinetoplastid parasite responsible for visceral leishmaniasis or kala-azar. Inhibition of this enzyme has shown promise as a strategy for therapy against visceral leishmaniasis. However, current treatment options suffer from limitations related to effectiveness, cost, and side effects. To address these challenges, computational methods have been employed in this study to investigate the inhibition of DNA topoisomerase I (LdTopo I) by phytochemicals derived from Indian medicinal plants known for their anti-leishmanial activity. A library of phytochemicals and known inhibitors was assembled, and virtual screening based on docking binding affinities was conducted to identify potent phytochemical inhibitors. To assess the drug-likeness of the docked phytochemicals, their physicochemical properties were predicted. Additionally, molecular dynamics (MD) simulations were performed on the docked complexes for a duration of 100 ns to evaluate their stability, intermolecular interactions, and dynamic behavior. Among all the docked phytochemicals, three compounds, namely CID23266147 (withanolide N), CID5488537 (fagopyrine), and CID100947536 (isozeylanone), exhibited the highest inhibitory potential against LdTopo I. These findings hold promise for the development of novel inhibitors targeting LdTopo I, which could potentially lead to improved therapies for visceral leishmaniasis.Communicated by Ramaswamy H. Sarma.