QSAR and molecular docking for the search of AOX inhibitors: a rational drug discovery approach
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QSAR and molecular docking for the search of AOX inhibitors: a rational drug discovery approach Alicia Rosell‑Hidalgo1 · Luke Young1 · Anthony L. Moore1 · Taravat Ghafourian1,2 Received: 21 January 2020 / Accepted: 12 November 2020 © The Author(s) 2020
Abstract The alternative oxidase (AOX) is a monotopic diiron carboxylate protein that catalyses the oxidation of ubiquinol and the reduction of oxygen to water. Although a number of AOX inhibitors have been discovered, little is still known about the ligand–protein interaction and essential chemical characteristics of compounds required for a potent inhibition. Furthermore, owing to the rapidly growing resistance to existing inhibitors, new compounds with improved potency and pharmacokinetic properties are urgently required. In this study we used two computational approaches, ligand–protein docking and Quantitative Structure–Activity Relationships (QSAR) to investigate binding of AOX inhibitors to the enzyme and the molecular characteristics required for inhibition. Docking studies followed by protein–ligand interaction fingerprint (PLIF) analysis using the AOX enzyme and the mutated analogues revealed the importance of the residues Leu 122, Arg 118 and Thr 219 within the hydrophobic cavity. QSAR analysis, using stepwise regression analysis with experimentally obtained I C50 values as the response variable, resulted in a multiple regression model with a good prediction accuracy. The model highlighted the importance of the presence of hydrogen bonding acceptor groups on specific positions of the aromatic ring of ascofuranone derivatives, acidity of the compounds, and a large linker group on the compounds on the inhibitory effect of AOX. Keywords AOX · Ascofuranone · Molecular docking · QSAR · Alternative oxidase · Fungicide
Introduction The alternative oxidase (AOX) is a non-protonmotive ubiquinol–oxygen oxidoreductase that couples the oxidation of ubiquinol with the complete reduction of oxygen to water in a manner insensitive to inhibitors of the cytochrome oxidase pathway [1, 2]. In eukaryotes, AOXs are located attached to the inner surface of the inner membrane of the Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10822-020-00360-8) contains supplementary material, which is available to authorized users. * Taravat Ghafourian [email protected] Anthony L. Moore [email protected] 1
Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9QG, UK
School of Life Sciences, Faculty of Creative Arts, Technologies and Science, University of Bedfordshire, Luton, Bedfordshire LU1 3JU, UK
2
mitochondria, on the substrate-side of the cytochrome bc1 complex [3]. Historically, the AOX was first identified in thermogenic plants, however the gene encoding this protein has been found in all higher plants and also throughout other kingdoms such as the fungal, protist and in prokaryotes [4]. Homologs have also been identified in α-proteobacteria
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