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 IC50 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.
Highlights
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]
The AOX is widespread among some important human pathogenic parasites such as Blastocystis hominis, the most common eukaryotic microbe found in the human gut [6], Paracoccidioides brasiliensis, the pathogenic fungus responsible for paracoccidioidomycosis in humans [7], or Candida albicans, an opportunistic human pathogen [8]
The protein–ligand interaction fingerprint (PLIF) tool within MOE summarizes the interactions of the compounds with the AOX ligand binding residues using a fingerprint scheme, in which interactions are classified according to the residue of origin (Fig. 4)
Summary
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]. The AOX was first identified in thermogenic plants, the gene encoding this protein has been found in all higher plants and throughout other kingdoms such as the fungal, protist and in prokaryotes [4]. The AOX is widespread among some important human pathogenic parasites such as Blastocystis hominis, the most common eukaryotic microbe found in the human gut [6], Paracoccidioides brasiliensis, the pathogenic fungus responsible for paracoccidioidomycosis in humans [7], or Candida albicans, an opportunistic human pathogen [8]. The AOX is found in Cryptosporidium parvum, one of the most widespread intestinal parasites, responsible for diarrheal disease cryptosporidiosis, for which there is no effective treatment currently available. Cryptosporidiosis represents a potential fatal disease especially in opportunistic infections
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