Exploring Subsite Selectivity within Plasmodium vivax N-Myristoyltransferase Using Pyrazole-Derived Inhibitors

Area of Science:

• Medicinal Chemistry
• Parasitology
• Structural Biology

Background:

• N-myristoyltransferase (NMT) is a validated antimalarial drug target.
• Achieving high selectivity between Plasmodium vivax NMT (PvNMT) and human NMT is crucial for drug development.
• Previous research indicated the feasibility of selective PvNMT inhibition.

Purpose of the Study:

• To identify novel antimalarial compounds targeting PvNMT with high selectivity.
• To explore structure-activity relationships by modifying pyrazole-based inhibitors.
• To elucidate mechanisms of selectivity through structural and biochemical analyses.

Main Methods:

• Synthesis and chemical modification of pyrazole-based NMT inhibitors.
• In vitro biochemical assays to determine enzyme inhibition and selectivity indices.
• Cocrystallization of PvNMT with selective inhibitors and X-ray diffraction analysis.

Main Results:

• Compounds with selectivity index values ranging from 0.8 to 125.3 were identified.
• Cocrystal structures revealed how inhibitor modifications, like a naphthalene moiety, affect binding interactions and protein conformation.
• Structural data indicated that bulky groups can alter inhibitor positioning and binding site interactions by interacting with protein-bound water molecules.

Conclusions:

• The study provides a conceptual framework for designing highly selective NMT inhibitors against Plasmodium vivax.
• Structure-activity relationship data guides future optimization of antimalarial drug candidates.
• Understanding inhibitor-water interactions is key to achieving potent and selective drug design.