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
Kangsa Amporndanai,
Nattapon Pinthong,
Paul M. O’Neill,
W. David Hong,
Richard K. Amewu,
Chandrakala Pidathala,
Neil G. Berry,
Suet C. Leung,
Stephen A. Ward,
Giancarlo A. Biagini,
S. Samar Hasnain,
Svetlana V. Antonyuk
Affiliations
Kangsa Amporndanai
Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK
Nattapon Pinthong
Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK
Paul M. O’Neill
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
W. David Hong
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Richard K. Amewu
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Chandrakala Pidathala
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Neil G. Berry
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Suet C. Leung
Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK
Stephen A. Ward
Centre for Drugs and Diagnostics, Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
Giancarlo A. Biagini
Centre for Drugs and Diagnostics, Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK
S. Samar Hasnain
Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK
Svetlana V. Antonyuk
Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK
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.
