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 Leishmania donovani, 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 Leishmania donovani
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.