Explainable Machine Learning for Property Predictions in Compound Optimization

The prediction of compound properties from chemical structure is a main task for machine learning (ML) in medicinal chemistry. ML is often applied to large data sets in applications such as compound screening, virtual library enumeration, or generative chemistry. Albeit desirable, a detailed understanding of ML model decisions is typically not required in these cases. By contrast, compound optimization efforts rely on small data sets to identify structural modifications leading to desired property profiles. In this situation, if ML is applied, one usually is reluctant to make decisions based on predictions that cannot be rationalized. Only few ML methods are interpretable. However, to yield insights into complex ML model decisions, explanatory approaches can be applied. Herein, methodologies for better understanding of ML models or explaining individual predictions are reviewed and current challenges in integrating ML into medicinal chemistry programs as well as future opportunities are discussed.