A critical component of small molecule drug discovery is hit expansion, the process of designing, synthesizing and testing candidate compounds active against a certain protein target, when some active compounds against this target ("hits") are already known. A successful drug discovery campaign should generate a diverse set of active compounds to de-risk the absorption, distribution, metabolism, elimination, toxicity (ADMET) challenges. Hit expansion has been a difficult task for several reasons, including a combinatorial explosion of the number of chemically-meaningful modifications of bioactive molecules, a need to ensure synthetic accessibility of new compounds, limiting possible modifications to minor changes in R-groups, and complex relationships between the structure of molecules and their multiple properties relevant for drug optimization.