Datasets Construction and Development of QSAR Models for Predicting Micronucleus In Vitro and In Vivo Assay Outcomes

Abstract

In silico (quantitative) structure–activity relationship modeling is an approach that provides a fast and cost-effective alternative to assess the genotoxic potential of chemicals. However, one of the limiting factors for model development is the availability of consolidated experimental datasets. In the present study, we collected experimental data on micronuclei in vitro and in vivo, utilizing databases and conducting a PubMed search, aided by text mining using the BioBERT large language model. Chemotype enrichment analysis on the updated datasets was performed to identify enriched substructures. Additionally, chemotypes common for both endpoints were found. Five machine learning models in combination with molecular descriptors, twelve fingerprints and two data balancing techniques were applied to construct individual models. The best-performing individual models were selected for the ensemble construction. The curated final dataset consists of 981 chemicals for micronuclei in vitro and 1309 for mouse micronuclei in vivo, respectively. Out of 18 chemotypes enriched in micronuclei in vitro, only 7 were found to be relevant for in vivo prediction. The ensemble model exhibited high accuracy and sensitivity when applied to an external test set of in vitro data. A good balanced predictive performance was also achieved for the micronucleus in vivo endpoint.