High throughput structural genomics such as pursued by the structural genomics consortium leads to a constantly increasing number of high quality structures of proteins. Besides supporting drug discovery and development, this also allows to consider structure-based approaches for in silico toxicology. Here we present our modelling efforts for mitochondrial respiratory complexes I, II, and III designed to gain insights into the ligand binding events as well as to learn what triggers ligand-complex selectivity. The basis for the study is a comprehensive data set of respiratory complex I, II, and III inhibitors collected in the framework of the EU-ToxRisk project (http://www.eu-toxrisk.eu).<br/>While for human complex II a high resolution structure has not been resolved up to now, available structures of complex I and III allow to utilize structure-based approaches. In case of complex I, aligning the structure of Rhodobacter capsulatus with the available cyro-EM structure of the human analog allowed to define a proper binding site for complex I inhibitors. Docking of 5 compounds into this site followed by common scaffold clustering of all poses identified two clusters where rotenone and deguelin share the same binding mode. In case of human complex III, we face the advantage that the analogous bovine structure is available in a conformation bound to antimycin A. Aligning the bovine structure with the human one allowed to reproduce the antimycin A binding mode in the human protein.<br/>Analysis of the binding modes aids in the understanding of the molecular basis triggering interaction and, ultimately, will lead to better prediction of mitochondrial toxicity of compounds.

Inhibitors of the mitochondrial respiratory complex - Structure-based prediction of toxicity

256th National Meeting (2018)

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