Targeting the Ubiquinol-Reduction (Q i ) Site of the Mitochondrial Cytochrome bc 1 Complex for the Development of Next Generation Quinolone Antimalarials.

Antimalarials targeting the ubiquinol-oxidation (Q _o ) site of the Plasmodium falciparum bc ₁ complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Q _o site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc ₁ complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc ₁ . Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian's equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Q _i sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc ₁ with improved antimalarial properties.