Screening of potential inhibitors of Leishmania major N-myristoyltransferase from Azadirachta indica phytochemicals for leishmaniasis drug discovery by molecular docking, molecular dynamics simulation and density functional theory methods

Leishmaniasis is one of the most neglected parasitic diseases worldwide. The toxicity of current drugs used for its treatment is a major obstacle to their effectiveness, necessitating the discovery and development of new therapeutic agents for better disease control. In Leishmania parasites, N-Myristoyltransferase (NMT) has been identified as a promising target for drug development. Thus, exploring well-known medicinal plants such as Azadirachta indica and their phytochemicals can offer a diverse range of treatment options, potentially leading to disease prevention and control. To assess the therapeutic potential of these compounds, their ADMET prediction and drug-likeness properties were analyzed. The top 4 compounds were selected which had better and significantly low binding energy than the reference molecule QMI. Based on the binding energy score of the top compounds, the results show that Isonimocinolide has the highest binding affinity (-9.8 kcal/mol). In addition, a 100 ns MD simulation of the four best compounds showed that Isonimocinolide and Nimbolide have good stability with LmNMT. These compounds were then subjected to MMPBSA (last 30 ns) calculation to analyze protein-ligand stability and dynamic behavior. Nimbolide and Meldenin showed lowest binding free energy i.e. -84.301 kJ/mol and -91.937 kJ/mol respectively. DFT was employed to calculate the HOMO-LUMO energy gap, global reactivity parameters, and molecular electrostatic potential of all hit molecules. The promising results obtained from MD simulations and MMPBSA analyses provide compelling evidence for the potential use of these compounds in future drug development efforts for the treatment of leishmaniasis.Communicated by Ramaswamy H. Sarma