SynGFN: learning across chemical space with generative flow-based molecular discovery.

Abstract

In recent years, artificial intelligence has advanced the design-make-test-analyze cycle, transforming molecular discovery. Despite these advances, the compartmentalized approach to computer-aided molecular design and synthesis remains a critical bottleneck, limiting further optimization of the design-make-test-analyze cycle. Here, to this end, we introduce SynGFN, which models molecular design as a cascade of simulated chemical reactions, enabling the assembly of molecules from synthesizable building blocks. SynGFN features two key ingredients: (1) a hierarchically pretrained policy network that accelerates learning across diverse distributions of desirable molecules in chemical spaces, and (2) a multifidelity acquisition framework to alleviate the cost of reward evaluations. These technical developments collectively endow SynGFN with the capability to explore a chemical space up to an order of magnitude larger (measured in terms of #Circles) than that of other synthesis-aware generative models, while identifying the most diverse, synthesizable and high-performance molecules. We demonstrate SynGFN's potential impacts by designing inhibitors for GluN1/GluN3A, a therapeutic target for neuropsychiatric disorders.