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

Area of Science:

• Medicinal Chemistry and Drug Discovery
• Parasitology and Tropical Diseases
• Computational Biology and Cheminformatics

Background:

• Neglected tropical diseases (NTDs) disproportionately affect impoverished populations, impacting global health and economies.
• Leishmaniasis, human African trypanosomiasis (HAT), and malaria share high incidence and increase NTD infection risk.
• N-myristoyltransferase (NMT) is a validated drug target for these diseases.

Purpose of the Study:

• To review epidemiological data for NTDs and related diseases.
• To highlight the importance of N-myristoyltransferase (NMT) as a drug target.
• To present novel chemical scaffolds and computational insights for new drug development against leishmaniasis, HAT, and malaria.

Main Methods:

• Computational methods were employed to identify potential drug scaffolds.
• Biological assays were conducted to validate the efficacy of identified compounds.
• Structure-activity relationships were analyzed through interactions with specific enzyme residues.

Main Results:

• Several scaffolds, including thiochromene, pyrazole, thienopyridine, oxadiazole, benzothiophene, and quinoline, showed promise.
• Aminoacylpyrrolidine derivative 13 demonstrated potent activity against Leishmania donovani NMT (IC50 = 1.6 nM).
• Pyrazole analog 23 exhibited significant activity against Plasmodium vivax NMT (IC50 = 9.48 nM).

Conclusions:

• NMT inhibitors represent a viable strategy for combating leishmaniasis, HAT, and malaria.
• Specific interactions with NMT residues (e.g., Val81, Tyr211, Lys25) are crucial for drug selectivity and activity.
• The findings provide valuable insights for the rational design of innovative anti-parasitic drugs.