Antimalarial 4(1H)-pyridones bind to the Qisite of cytochromebc1

Capper, Michael J., O’Neill, Paul M., Fisher, Nicholas, Strange, Richard W., Moss, Darren M., Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Berry, Neil G., Lawrenson, Alexandre S., Hasnain, S. Samar, Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595 and Antonyuk, Svetlana V. (2015) 'Antimalarial 4(1H)-pyridones bind to the Qisite of cytochromebc1'. Proceedings of the National Academy of Sciences, Vol 112, Issue 3, pp. 755-760.

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Abstract

Cytochrome bc1 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 Qo site (one of two potential binding sites within cytochrome bc1) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc1 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:	QY Clinical Pathology > Blood. Blood Chemistry > QY 490 Enzymes QY Clinical Pathology > QY 25 Laboratory techniques and procedure WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 190 Hemoglobin and other hemeproteins. Porphyrins (Associated with hemoglobin)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1073/pnas.1416611112
Depositing User:	Martin Chapman
Date Deposited:	08 Jan 2015 16:07
Last Modified:	07 Jun 2018 12:42
URI:	https://archive.lstmed.ac.uk/id/eprint/4723

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