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Publication Abstract from PubMed

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.

Targeting the Ubiquinol-Reduction (Q(i)) Site of the Mitochondrial Cytochrome bc(1) Complex for the Development of Next Generation Quinolone Antimalarials.,Amporndanai K, Pinthong N, O'Neill PM, Hong WD, Amewu RK, Pidathala C, Berry NG, Leung SC, Ward SA, Biagini GA, Hasnain SS, Antonyuk SV Biology (Basel). 2022 Jul 25;11(8):1109. doi: 10.3390/biology11081109. PMID:35892964^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.