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Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1

Capper, MJ and O'Neill, PM and Fisher, N and Strange, RW and Moss, D and Ward, SA and Berry, NG and Lawrenson, AS and Hasnain, SS and Biagini, GA and Antonyuk, SV (2015) 'Antimalarial 4(1H)-pyridones bind to the Qi site of cytochrome bc1.' Proceedings of the National Academy of Sciences of the United States of America, 112 (3). 755 - 760. ISSN 0027-8424

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Cytochrome bc<inf>1</inf> is a proven drug target in the prevention and treatment of malaria. The rise in drug-resistant strains of Plasmodium falciparum, the organism responsible for malaria, has generated a global effort in designing new classes of drugs. Much of the design/redesign work on overcoming this resistance has been focused on compounds that are presumed to bind the Q<inf>o</inf> site (one of two potential binding sites within cytochrome bc<inf>1</inf>) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc<inf>1</inf> complex with the 4(1H)-pyridone class of inhibitors, GSK932121 and GW844520, that have been shown to be potent antimalarial agents in vivo, revealed that these inhibitors do not bind at the Qo site but bind at the Qi site. The discovery that these compounds bind at the Qi site may provide a molecular explanation for the cardiotoxicity and eventual failure of GSK932121 in phase-1 clinical trial and highlight the need for direct experimental observation of a compound bound to a target site before chemical optimization and development for clinical trials. The binding of the 4(1H)-pyridone class of inhibitors to Qi also explains the ability of this class to overcome parasite Qo-based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles.

Item Type: Article
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science and Health > Life Sciences, School of
Depositing User: Richard Strange
Date Deposited: 08 Mar 2016 09:47
Last Modified: 20 Aug 2019 12:15

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