STRUCTURAL FEATURES AND INTERACTIONS OF KNOWN INHIBITORS OF RESPIRATORY COMPLEXES

The electron transport chain (ETC) is essential for biophysical energy transduction. The inhibition of complexes II and III (CxII and CxIII, respectively) of this chain is widely used to combat pathogens in human diseases and in agriculture, with great biomedical and biotechnological interest. In recent years, our research group has employed computer simulations to study the molecular mechanisms of activity and inhibition of these respiratory complexes. Here, we present a detailed structural analysis of the binding modes and molecular interactions of protein-inhibitor complexes for a set of commercial inhibitors of respiratory CxII and CxIII, combining experimental structures deposited in the PDB with docking and classical molecular dynamics simulation methods. We found 50 and 63 experimental protein-inhibitor structures for CxII and CxIII, respectively. In at least 55% of these structures, the coenzyme Q substrate binding site is competitively inhibited, mainly by molecules of the phenyl-benzamide and carboxin classes for CxII, and by stigmatellin and oxazolidine-dione classes for CxIII. Hydrogen bonds, often assisted by bridging water molecules, and hydrophobic contacts are the main stabilizing interactions found. We hope that this analysis will be used in the future to propose modifications and develop inhibitors with better potency and lower human toxicity.