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GNF ID 100602: Identification of inhibitors for putative malaria drug targets amongst novel antimalarial compounds

Kuhen, Kelli and Gilligan, James and Gagaring, Kerstin Mae and Borboa, Rachel and Francek, Carolyn and Zhong, Chen and Dagostino, Eleanor and Justin, Stockmyer and Yu, Wang and Brinker, Achim and Engels, Ingo and Taylor, Jennifer and Chatterjee, Arnab and Glynne, Richard and Kuhen, Kelli and Greg, Crowther and Stolz, Barbara (2010) GNF ID 100602: Identification of inhibitors for putative malaria drug targets amongst novel antimalarial compounds. Molecular and Biochemical Parasitology.

Abstract

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 P. falciparum, excluding targets which are inhibited by currently used drugs. A screen of commercially available libraries identified 5,655 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.

Item Type: Article
Additional Information: B. Stolz is NOT an author -- NVS contact person for GNF manuscript approval. This manuscript shall NOT be copied to the OAK internet.
Keywords: target-based drug development, enzyme activity assays, Malaria Box
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3108

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