Leveraging Consensus Docking Approaches for Human Mitochondrial Complexes I and III

Although recent progress has been made, structure-based methods such as molecular docking are still underexplored in the context of toxicity prediction. These approaches offer added value, particularly in addressing challenges such as activity cliffsi.e., caused by stereoisomerismthat are difficult to capture by conventional Quantitative Structure–Activity Relationship (QSAR) methods. In this study, we investigated the ability of docking scoring functions and protein–ligand interaction fingerprints to rank the potential hazard of compounds targeting the human mitochondrial complexes I and III (CI, NADH:ubiquinone oxidoreductase and CIII, cytochrome bc1 complex). We applied an induced fit docking protocol to account for binding site flexibility and performed a set of binding energy minimizations for rescoring of representative binding modes. Both individual scoring functions and consensus scoring approaches achieved acceptable rank correlation to experimentally derived data from CIII (Spearman r: 0.89 and 0.86). Moreover, consensus interaction fingerprints that combine molecular interactions from both docking outputs captured differences of inhibitor subtypes at CIII. Follow-up in vitro testing confirmed an isomerism-dependent activity cliff of E-/Z-Fenpyroximate at CI. These findings support the utility of using consensus docking and scoring as a screening-level tool for prioritizing compounds based on interpretable predicted relative binding affinities at CI and CIII.