N-Myristoyltransferase Inhibition in Parasitic Pathogens: Insights from Computer-Aided Drug Design

Neglected tropical diseases (NTDs) constitute a group of infectious diseases that severely affect the health of impoverished populations, and the health, economies, and health systems of affected countries. Leishmaniasis and human African trypanosomiasis (HAT) are particularly notable, and malaria, despite not being neglected, is part of the “big three” (HIV, tuberculosis, and malaria) with high incidence, increasing the probability of infection by NTDs. Therefore, efforts are ongoing in the search for new drugs targeting the enzyme N-myristoyltransferase (NMT), a potential drug target that has been explored. Thus, we provide a review here that highlights the epidemiological data for these diseases and the importance of discovering new drugs against these agents. Here, the importance of NMT and its inhibitors is clear, with this study highlighting thiochromene, pyrazole, thienopyridine, oxadiazole, benzothiophene, and quinoline scaffolds, identified by computational methods followed by biological assays to validate the findings; for example, this study shows the action of the aminoacylpyrrolidine derivative 13 against Leishmania donovani NMT (IC₅₀ of 1.6 nM) and the pyrazole analog 23 against Plasmodium vivax NMT (IC₅₀ of 9.48 nM), providing several insights that can be used in drug design in further work. Furthermore, the selectivity and improvement in activity are related to interactions with the residues Val⁸¹, Phe⁹⁰, Tyr²¹⁷, Tyr³²⁶, Tyr³⁴⁵, and Met⁴²⁰ for leishmaniasis (LmNMT); Tyr²¹¹, Leu⁴¹⁰, and Ser³¹⁹ for malaria (PvNMT); and Lys²⁵ and Lys³⁸⁹ for HAT (TbNMT). We hope our work provides valuable insights that research groups worldwide can use to search for innovative drugs to combat these diseases.