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Identification of Selective Inhibitors of Plasmodium N-Myristoyltransferase by High-Throughput Screening
Anke Harupa1,2,3, Laura De Las Heras2, Gonzalo Colmenarejo2
1Center for Infectious Disease Research , Seattle , Washington 98109 , United States.
Abstract:
New drugs that target Plasmodium species, the causative agents of malaria, are needed. The enzyme N-myristoyltransferase (NMT) is an essential protein, which catalyzes the myristoylation of protein substrates, often to mediate membrane targeting. We screened ∼1.8 million small molecules for activity against Plasmodium vivax (P. vivax) NMT. Hits were triaged based on potency and physicochemical properties and further tested against P. vivax and Plasmodium falciparum (P. falciparum) NMTs. We assessed the activity of hits against human NMT1 and NMT2 and discarded compounds with low selectivity indices. We identified 23 chemical classes specific for the inhibition of Plasmodium NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of P. vivax NMT with one compound revealed peptide binding pocket binding. Other compounds show a range of potential modes of action. Our data provide insight into the activity of a collection of selective inhibitors of Plasmodium NMT and serve as a starting point for subsequent medicinal chemistry efforts.
Insights
New malaria drugs targeting Plasmodium N-myristoyltransferase (NMT) were identified. Researchers screened millions of compounds, finding 23 classes selective for Plasmodium NMT over human NMT, offering new avenues for drug development.
Area of Science:
- Medicinal Chemistry
- Parasitology
- Drug Discovery
Background:
- Malaria remains a significant global health burden, necessitating novel therapeutic strategies.
- The enzyme N-myristoyltransferase (NMT) is crucial for the survival of Plasmodium parasites, making it a promising drug target.
- Existing antimalarial treatments face challenges due to drug resistance, highlighting the need for new drug classes.
Purpose of the Study:
- To identify novel small molecules that selectively inhibit Plasmodium N-myristoyltransferase (NMT).
- To discover new chemical scaffolds with potential as antimalarial agents.
- To provide a foundation for future medicinal chemistry optimization of Plasmodium NMT inhibitors.
Main Methods:
- Screening of approximately 1.8 million small molecules against Plasmodium vivax NMT.
- Hit compound triage based on potency, physicochemical properties, and selectivity against human NMT isoforms (NMT1 and NMT2).
- Cocrystallization of Plasmodium vivax NMT with an inhibitor to elucidate binding mode.
Main Results:
- Identification of 23 distinct chemical classes that selectively inhibit Plasmodium NMTs over human NMTs.
- Discovery of multiple novel chemical scaffolds with antimalarial potential.
- Structural analysis revealed that one inhibitor binds within the peptide-binding pocket of P. vivax NMT.
Conclusions:
- The study successfully identified selective inhibitors of Plasmodium NMT, offering promising starting points for antimalarial drug development.
- The identified compounds and novel scaffolds provide valuable chemical matter for further medicinal chemistry efforts.
- Targeting Plasmodium NMT represents a viable strategy for developing new drugs against malaria.
