Integrating Mechanistic and Toxicokinetic Information in Predictive Models of Cholestasis

Journal of Chemical Information and Modeling
Rodríguez-Belenguer Pablo, Mangas-Sanjuan Victor, Soria-Olivas Emilio, Pastor Manuel
DOI: 10.1021/acs.jcim.3c00945
PMID: 37660324
Keyword: bioinformatics and computational biology · peptides and proteins · quality management · structure activity relationship · therapeutics


Drug development involves the thorough assessment of the candidate’s safety and efficacy. In silico toxicology (IST) methods can contribute to the assessment, complementing in vitro and in vivo experimental methods, since they have many advantages in terms of cost and time. Also, they are less demanding concerning the requirements of product and experimental animals. One of these methods, Quantitative Structure-Activity Relationships (QSAR), has been proven successful in predicting simple toxicity end points but has more difficulties in predicting end points involving more complex phenomena. We hypothesize that QSAR models can produce better predictions of these end points by combining multiple QSAR models describing simpler biological phenomena and incorporating pharmacokinetic (PK) information, using quantitative in vitro to in vivo extrapolation (QIVIVE) models. In this study, we applied our methodology to the prediction of cholestasis and compared it with direct QSAR models. Our results show a clear increase in sensitivity. The predictive quality of the models was further assessed to mimic realistic conditions where the query compounds show low similarity with the training series. Again, our methodology shows clear advantages over direct QSAR models in these situations. We conclude that the proposed methodology could improve existing methodologies and could be suitable for being applied to other toxicity end points.