Amporndanai, Kangsa, Pinthong, Nattapon 
ORCID: 0000-0002-0740-9496, O'Neill, Paul M, Hong, W David, Amewu, Richard K ORCID: 0000-0002-4676-436X, Pidathala, Chandrakala, Berry, Neil G ORCID: 0000-0003-1928-0738, Leung, Suet C, Ward, Stephen A, Biagini, Giancarlo A et al (show 2 more authors)
(2022)
Targeting the Ubiquinol-Reduction (Q<sub>i</sub>) Site of the Mitochondrial Cytochrome <i>bc<sub>1</sub></i> Complex for the Development of Next Generation Quinolone Antimalarials.
BIOLOGY-BASEL, 11 (8).
1109-.
Abstract
Antimalarials targeting the ubiquinol-oxidation (Q<sub>o</sub>) site of the <i>Plasmodium falciparum</i> bc<sub>1</sub> complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Q<sub>o</sub> 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 <i>bc<sub>1</sub></i> 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 <i>Plasmodial</i> cytochrome <i>bc<sub>1</sub></i>. Our crystallographic studies have enabled comparison of an in-silico homology docking model of <i>P. falciparum</i> 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 <i>P. falciparum</i> Q<sub>i</sub> 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 <i>bc<sub>1</sub></i> with improved antimalarial properties.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | antimalarial, Plasmodium falciparum, atovaquone, drug resistance, quinolone, bc(1) inhibitor, crystallography, molecular modeling, homology modeling, mitochondria |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology Faculty of Science and Engineering > School of Physical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 16 Aug 2022 10:14 |
| Last Modified: | 19 Oct 2023 08:55 |
| DOI: | 10.3390/biology11081109 |
| Open Access URL: | https://doi.org/10.3390/biology11081109 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3161373 |
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