Optimal Molecular Design: Generative Active Learning Combining REINVENT with Precise Binding Free Energy Ranking Simulations.

Active learning (AL) is a specific instance of sequential experimental design and uses machine learning to intelligently choose the next data point or batch of molecular structures to be evaluated. In this sense, it closely mimics the iterative design-make-test-analysis cycle of laboratory experiments to find optimized compounds for a given design task. Here, we describe an AL protocol which combines generative molecular AI, using REINVENT, and physics-based absolute binding free energy molecular dynamics simulation, using ESMACS, to discover new ligands for two different target proteins, 3CL pro and TNKS2. We have deployed our generative active learning (GAL) protocol on Frontier, the world's only exa-scale machine. We show that the protocol can find higher-scoring molecules compared to the baseline, a surrogate ML docking model for 3CL pro and compounds with experimentally determined binding affinities for TNKS2. The ligands found are also chemically diverse and occupy a different chemical space than the baseline. We vary the batch sizes that are put forward for free energy assessment in each GAL cycle to assess the impact on their efficiency on the GAL protocol and recommend their optimal values in different scenarios. Overall, we demonstrate a powerful capability of the combination of physics-based and AI methods which yields effective chemical space sampling at an unprecedented scale and is of immediate and direct relevance to modern, data-driven drug discovery.