期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：3
页码：755-760
DOI：10.1073/pnas.1416611112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceX-ray crystallography greatly benefits drug discovery work by elucidating information about the binding of drug compounds to their target. Using this information, changes to the compounds can be made in a process known as rational drug design. Cytochrome bc1 is a proven drug target in the treatment and prevention of malaria, a disease that kills over half a million people each year and many compounds have been developed to inhibit cytochrome bc1. Here we show the binding of two such compounds in X-ray crystal structures, which reveal an unexpected binding site. This work opens up a new area for antimalarial research and reinforces the need for structural information in drug design. 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.
关键词：malaria ; cytochrome bc 1 ; drug discovery ; Plasmodium falciparum ; membrane protein
