Chemistry-informed molecular graph as reaction descriptor for machine-learned retrosynthesis planning

Infusing “chemical wisdom” should improve the data-driven approaches that rely exclusively on historical synthetic data for automatic retrosynthesis planning. For this purpose, we designed a chemistry-informed molecular graph (CIMG) to describe chemical reactions. A collection of key information that is most relevant to chemical reactions is integrated in CIMG:NMR chemical shifts as vertex features, bond dissociation energies as edge features, and solvent/catalyst information as global features. For any given compound as a target, a product CIMG is generated and exploited by a graph neural network (GNN) model to choose reaction template(s) leading to this product. A reactant CIMG is then inferred and used in two GNN models to select appropriate catalyst and solvent, respectively. Finally, a fourth GNN model compares the two CIMG descriptors to check the plausibility of the proposed reaction. A reaction vector is obtained for every molecule in training these models. The chemical wisdom of reaction propensity contained in the pretrained reaction vectors is exploited to autocategorize molecules/reactions and to accelerate Monte Carlo tree search (MCTS) for multistep retrosynthesis planning. Full synthetic routes with recommended catalysts/solvents are predicted efficiently using this CIMG-based approach.