Automated De Novo Design in Medicinal Chemistry: Which Types of Chemistry Does a Generative Neural Network Learn?

Artificial intelligence offers promising solutions for property prediction, compound design, and retrosynthetic planning, which are expected to significantly accelerate the search for pharmacologically relevant molecules. Here, we investigate aspects of artificial intelligence based de novo design pertaining to its integration into real-life workflows. First, different chemical spaces were used as training sets for reinforcement learning (RL) in combination with different reward functions. With the trained neuronal networks different biologically active molecules could be regenerated. Excluding molecules with substructures such as five-membered rings from training spaces nevertheless produced results containing these moieties. Furthermore, different scoring functions in RL were investigated and produced different design ensembles. In summary, some of these design proposals are close in chemical space to the query, thus supporting lead optimization, while 3D-shape or QSAR (quantitative structure-activity relationship) models produced significantly different proposals by sampling a broader region of the chemical space, thus supporting lead generation. Therefore, RL provides a good framework to tailored design approaches for different discovery phases.