Identification of Selective Inhibitors of <i>Plasmodium</i> N-Myristoyltransferase by High-Throughput Screening

Abstract

New drugs that target <i>Plasmodium</i> species, the causative agents of malaria, are needed. The enzyme <i>N</i>-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 <i>Plasmodium vivax</i> (<i>P. vivax</i>) NMT. Hits were triaged based on potency and physicochemical properties and further tested against <i>P. vivax</i> and <i>Plasmodium falciparum</i> (<i>P. falciparum</i>) 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 <i>Plasmodium</i> NMTs over human NMTs, including multiple novel scaffolds. Cocrystallization of <i>P. vivax</i> 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 <i>Plasmodium</i> NMT and serve as a starting point for subsequent medicinal chemistry efforts.