{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:31:40Z","timestamp":1792798300696,"version":"4.5.0"},"reference-count":78,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T00:00:00Z","timestamp":1658707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universities of Liverpool and Mahidol"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/biology11081109","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T21:20:59Z","timestamp":1658784059000},"page":"1109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials"],"prefix":"10.3390","volume":"11","author":[{"given":"Kangsa","family":"Amporndanai","sequence":"first","affiliation":[{"name":"Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK"},{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0740-9496","authenticated-orcid":false,"given":"Nattapon","family":"Pinthong","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK"},{"name":"Department of Protozoology, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"O\u2019Neill","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. David","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.","family":"Amewu","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"},{"name":"Department of Chemistry, School of Physical and Mathematical Sciences, University of Ghana, Accra P.O. Box LG 586, Ghana"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrakala","family":"Pidathala","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"},{"name":"Composite Interceptive Med-Science Laboratories Pvt. Ltd., Bengaluru 60099, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1928-0738","authenticated-orcid":false,"given":"Neil G.","family":"Berry","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suet C.","family":"Leung","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Liverpool, Liverpool L69 7ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Ward","sequence":"additional","affiliation":[{"name":"Centre for Drugs and Diagnostics, Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6356-6595","authenticated-orcid":false,"given":"Giancarlo A.","family":"Biagini","sequence":"additional","affiliation":[{"name":"Centre for Drugs and Diagnostics, Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool L3 5QA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. Samar","family":"Hasnain","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2779-9946","authenticated-orcid":false,"given":"Svetlana V.","family":"Antonyuk","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Group, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool L69 7ZB, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,25]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021). 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