Details

Autor(en) / Beteiligte

• Capper, Michael J.
• O’Neill, Paul M.
• Fisher, Nicholas
• Strange, Richard W.
• Moss, Darren
• Ward, Stephen A.
• Berry, Neil G.
• Lawrenson, Alexandre S.
• Hasnain, S. Samar
• Biagini, Giancarlo A.
• Antonyuk, Svetlana V.

Titel

Antimalarial 4(1H)-pyridones bind to the Q i site of cytochrome bc 1

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-01, Vol.112 (3), p.755-760

Erscheinungsjahr

2015

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Significance X-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 bc 1 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 bc 1 . 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 bc 1 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 o site (one of two potential binding sites within cytochrome bc 1 ) using the known crystal structure of this large membrane-bound macromolecular complex via in silico modeling. Cocrystallization of the cytochrome bc 1 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 Q o site but bind at the Q i site. The discovery that these compounds bind at the Q i 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 Q i also explains the ability of this class to overcome parasite Q o -based atovaquone resistance and provides critical structural information for future design of new selective compounds with improved safety profiles.