ADMET evaluation in drug discovery: 21. Application and industrial validation of machine learning algorithms for...

The Caco-2 cell model has been widely used to assess the intestinal permeability of drug candidates in vitro, owing to its morphological and functional similarity to human enterocytes. While Caco-2 cell assay is considered safe and cost-effective, it is also characterized by being time-consuming. Therefore, computational models that achieve high accuracies in predicting Caco-2 permeability are crucial for enhancing the efficiency of oral drug development. In this study, we conducted an in-depth analysis of the characteristics of an augmented Caco-2 permeability dataset, and evaluated a diverse range of machine learning algorithms in combination with different molecular representations. The results indicated that XGBoost generally provided better predictions than comparable models for the test sets. In addition, we investigated the transferability of machine learning models trained on publicly available data to internal pharmaceutical industry datasets. Our findings, based on the Shanghai Qilu's in-house dataset, showed that the boosting models retained a degree of predictive efficacy when applied to industry data. Furthermore, Y-randomization test and applicability domain analysis were employed to assess the robustness and generalizability of these models. Matched Molecular Pair Analysis (MMPA) was utilized to extract chemical transformation rules. We believe that the model developed in this study could represent a reliable tool for assessing Caco-2 permeability during early-stage drug discovery and the chemical transformation rules derived here could provide insights for optimizing Caco-2 permeability.Scientific contributionA comprehensive validation of various machine learning algorithms combined with diverse molecular representations on a large dataset for predicting Caco-2 permeability was reported. The transferability of machine learning models trained on publicly available data to internal pharmaceutical industry datasets was also investigated. Matched molecular pair analysis was carried out to provide reasonable suggestions for researchers to improve the Caco-2 permeability of compounds.