In Need of Bias Control: Evaluating Chemical Data for Machine Learning in Structure-Based Virtual Screening.

Reports of successful applications of machine learning (ML) methods in structure-based virtual screening (SBVS) are increasing. ML methods such as convolutional neural networks show promising results and often outperform traditional methods such as empirical scoring functions in retrospective validation. However, trained ML models are often treated as black boxes and are not straightforwardly interpretable. In most cases, it is unknown which features in the data are decisive and whether a model's predictions are right for the right reason. Hence, we re-evaluated three widely used benchmark data sets in the context of ML methods and came to the conclusion that not every benchmark data set is suitable. Moreover, we demonstrate on two examples from current literature that bias is learned implicitly and unnoticed from standard benchmarks. On the basis of these results, we conclude that there is a need for eligible validation experiments and benchmark data sets suited to ML for more bias-controlled validation in ML-based SBVS. Therefore, we provide guidelines for setting up validation experiments and give a perspective on how new data sets could be generated.