Identification of Selective Inhibitors of N-Myristoyltransferase by High-Throughput Screening.

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