Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

The efficacy of most marketed antimalarial drugs has been compromised by evolution of parasite resistance, underscoring an urgent need to find new drugs with new mechanisms of action. We have taken a high-throughput approach toward identifying novel antimalarial chemical inhibitors of prioritized drug targets for Plasmodium falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5655 low molecular weight compounds that inhibit growth of P. falciparum cultures with EC50 values below 1.25 μM. These compounds were then tested in 384- or 1536-well biochemical assays for activity against nine Plasmodium enzymes: adenylosuccinate synthetase (AdSS), choline kinase (CK), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), glutamate dehydrogenase (GDH), guanylate kinase (GK), N-myristoyltransferase (NMT), orotidine 5′-monophosphate decarboxylase (OMPDC), farnesyl pyrophosphate synthase (FPPS) and S-adenosylhomocysteine hydrolase (SAHH). These enzymes were selected using TDRtargets.org, and are believed to have excellent potential as drug targets based on criteria such as their likely essentiality, druggability, and amenability to high-throughput biochemical screening. Six of these targets were inhibited by one or more of the antimalarial scaffolds and may have potential use in drug development, further target validation studies and exploration of P. falciparum biochemistry and biology.

Graphical abstract. Thousands of antimalarial compounds were tested against nine potential Plasmodium drug targets. Six of the targets, including S-adenosylhomocysteine hydrolase (SAHH), were inhibited by antimalarial scaffolds, which may have use in target exploration and validation.Figure optionsDownload full-size imageDownload high-quality image (62 K)Download as PowerPoint slideResearch highlights▶ Inhibitors of six potential Plasmodium drug targets were identified. ▶ These inhibitors may be used as “tool compounds” to probe the corresponding enzymes. ▶ Most antimalarial compounds’ modes of action remain elusive.