Identification of mitochondrial toxicants by combined in silico and in vitro studies – A structure-based view on the adverse outcome pathway

Author(s)
Florentina Troger, Johannes Delp, Melina Funke, Wanda van der Stel, Claire Colas, Marcel Leist, Bob van de Water, Gerhard F. Ecker
Abstract

Drugs that modulate mitochondrial function can cause severe adverse effects. Unfortunately, mitochondrial toxicity is often not detected in animal models, which stresses the need for predictive in silico approaches. In this study we present a model for predicting mitochondrial toxicity focusing on human mitochondrial respiratory complex I (CI) inhibition by combining structure-based methods with machine learning. The structure-based studies are based on CI inhibition by the pesticide rotenone, which is known to induce parkinsonian motor deficits, and its analogue deguelin. After predicting a common binding mode for these two compounds using induced-fit docking, two structure-based pharmacophore models were created and used for virtual screening of DrugBank and the Chemspace library. The hit list was further refined by three different machine learning models, and the top ranked compounds were selected for experimental testing. Using a tiered approach, the compounds were tested in three distinct in vitro assays, which led to the identification of three specific CI inhibitors. These results demonstrate that risk assessment and hazard analysis can benefit from combining structure-based methods and machine learning.

Organisation(s)
Department of Pharmaceutical Chemistry
Journal
Computational Toxicology
Volume
14
Pages
100123
No. of pages
1
ISSN
2468-1113
DOI
https://doi.org/10.1016/j.comtox.2020.100123
Publication date
05-2020
Peer reviewed
Yes
Austrian Fields of Science 2012
Toxicology
Keywords
Portal url
https://ucris.univie.ac.at/portal/en/publications/identification-of-mitochondrial-toxicants-by-combined-in-silico-and-in-vitro-studies--a-structurebased-view-on-the-adverse-outcome-pathway(e70f7222-17e4-40c0-b043-c291c2d548a2).html