Leveraging Consensus Docking Approaches for Human Mitochondrial Complexes I and III

Author(s)

Karin Grillberger, Viktoria Magel, Marcel Leist, Gerhard F Ecker

Abstract

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 bc

1 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.

Organisation(s)

Department of Pharmaceutical Sciences

External organisation(s)

Universität Konstanz

Journal

Chemical Research in Toxicology

ISSN

0893-228X

DOI

https://doi.org/10.1021/acs.chemrestox.5c00348

Publication date

12-2025

Peer reviewed

Yes

Austrian Fields of Science 2012

301207 Pharmaceutical chemistry, 301211 Toxicology

Portal url

https://ucrisportal.univie.ac.at/en/publications/db2c57dc-c36a-49d8-911a-4274e565c523