Targeting the Ubiquinol-Reduction (Q<inf>i</inf>) Site of the Mitochondrial Cytochrome bc<inf>1</inf> Complex for the Development of Next Generation Quinolone Antimalarials
1
Issued Date
2022-08-01
Resource Type
eISSN
20797737
Scopus ID
2-s2.0-85137371468
Journal Title
Biology
Volume
11
Issue
8
Rights Holder(s)
SCOPUS
Bibliographic Citation
Biology Vol.11 No.8 (2022)
Suggested Citation
Amporndanai K., Pinthong N., O’Neill P.M., Hong W.D., Amewu R.K., Pidathala C., Berry N.G., Leung S.C., Ward S.A., Biagini G.A., Hasnain S.S., Antonyuk S.V. Targeting the Ubiquinol-Reduction (Q<inf>i</inf>) Site of the Mitochondrial Cytochrome bc<inf>1</inf> Complex for the Development of Next Generation Quinolone Antimalarials. Biology Vol.11 No.8 (2022). doi:10.3390/biology11081109 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/83640
Title
Targeting the Ubiquinol-Reduction (Q<inf>i</inf>) Site of the Mitochondrial Cytochrome bc<inf>1</inf> Complex for the Development of Next Generation Quinolone Antimalarials
Other Contributor(s)
Abstract
Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo 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 bc1 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 bc1. 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 Qi 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 bc1 with improved antimalarial properties.