Investigation of Potential Inhibitors of N‐Myristoyltransferase in Leishmania amazonensis: A Computational and Experimental Study

Leishmaniasis, a disease caused by Leishmania parasites, poses a significant health threat globally, particularly in Latin America and Brazil. Leishmania amazonensis is an important species because it is associated with both cutaneous leishmaniasis and an atypical visceral form. Current treatments are hindered by toxicity, resistance, and high cost, driving the need for new therapeutic targets and drugs. N‐myristoyltransferase (NMT) is an important anti‐leishmanial target. N‐myristoyltransferase (NMT) is an important target in Leishmania parasites, as it plays a crucial role in the process of myristoylation, a lipid modification that involves the attachment of myristate, a 14‐carbon saturated fatty acid, to the N‐terminus of specific proteins. In this work, a shape‐based modeling approach was employed to identify potential NMT inhibitors in Leishmania amazonensis . Using a pyrazole sulphonamide as a reference ligand, a five‐feature shape‐based model was developed and validated. Virtual screening of the DIVERSet EXP and CL libraries (~1 million compounds) prioritized the top 500 ranked molecules per subset based on the TanimotoCombo score. Molecular docking studies identified the three highest‐ranking compounds from each subset based on ChemPLP scores and docking pose consistency. Among the selected ligands, CL 54016012, EXP 6689657, and EXP 9226834 exhibited the most favorable binding interactions, with CL 54016012 forming stable hydrogen bonds with Tyr80, Tyr217, and Tyr345. Molecular dynamics (MD) simulations indicated that ligand binding did not significantly alter NMT structural stability, although variations in binding energy and hydrogen bond were observed. CL 54016012 demonstrated the highest docking score, optimal RMSD stability, and the lowest predicted IC50 value (19.81 μM), suggesting its potential as a lead compound. In vitro cytotoxicity assays revealed that CL 54016012, CL 74995016, and EXP 6689657 reduced L. amazonensis viability in a dose‐dependent manner, placing them as promising candidates for further investigation in anti‐leishmanial drug development.