Integrating Reaction Schemes, Reagent Databases, and Virtual Libraries into Fragment-Based Design by Reinforcement Learning.

Abstract

Lead optimization supported by artificial intelligence (AI)-based generative models has become increasingly important in drug design. Success factors are reagent availability, novelty, and the optimization of multiple properties. Directed fragment-replacement is particularly attractive, as it mimics medicinal chemistry tactics. Here, we present variations of fragment-based reinforcement learning using an actor-critic model. Novel features include freezing fragments and using reagents as the fragment source. Splitting molecules according to reaction schemes improves synthesizability, while tuning network output probabilities allows us to balance novelty versus diversity. Combining fragment-based optimization with virtual library encodings allows the exploration of large chemical spaces with synthesizable ideas. Collectively, these enhancements influence design toward high-quality molecules with favorable profiles. A validation study using 15 pharmaceutically relevant targets reveals that novel structures are obtained for most cases, which are identical or related to independent validation sets for each target. Hence, these modifications significantly increase the value of fragment-based reinforcement learning for drug design. The code is available on GitHub: https://github.com/Sanofi-Public/IDD-papers-fragrl.