1. Identification of a non-competitive inhibitor of Plasmodium falciparum aspartate transcarbamoylase
- Author
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Alexander Dömling, Fernando de Assis Batista, Matthew Groves, George Chamoun, Carsten Wrenger, Soraya S Bosch, Chao Wang, Paul D Kruithof, Jingyao Li, Sergey Lunev, Marleen Linzke, Drug Design, and Medicinal Chemistry and Bioanalysis (MCB)
- Subjects
0301 basic medicine ,Plasmodium falciparum ,Allosteric regulation ,Biophysics ,Crystallography, X-Ray ,Biochemistry ,03 medical and health sciences ,Non-competitive inhibition ,Catalytic Domain ,Drug Discovery ,Aspartate Carbamoyltransferase ,Journal Article ,Humans ,Enzyme Inhibitors ,Malaria, Falciparum ,MALÁRIA ,Molecular Biology ,Antiparasitic Agents ,030102 biochemistry & molecular biology ,biology ,Drug discovery ,Chemistry ,Active site ,Cell Biology ,biology.organism_classification ,Antiparasitic agent ,Molecular Docking Simulation ,Aspartate carbamoyltransferase ,030104 developmental biology ,Pyrimidine metabolism ,biology.protein - Abstract
Aspartate transcarbamoylase catalyzes the second step of de-novo pyrimidine biosynthesis. As malarial parasites lack pyrimidine salvage machinery and rely on de-novo production for growth and proliferation, this pathway is a target for drug discovery. Previously, an apo crystal structure of aspartate transcarbamoylase from Plasmodium falciparum (PfATC) in its T-state has been reported. Here we present crystal structures of PfATC in the liganded R-state as well as in complex with the novel inhibitor, 2,3-napthalenediol, identified by high-throughput screening. Our data shows that 2,3-napthalediol binds in close proximity to the active site, implying an allosteric mechanism of inhibition. Furthermore, we report biophysical characterization of 2,3-napthalenediol. These data provide a promising starting point for structure based drug design targeting PfATC and malarial de-novo pyrimidine biosynthesis.
- Published
- 2018