Hybridizing organic chemistry and synthetic biology reaction networks for optimizing synthesis routes

Computer assisted synthesis planning (CASP) accelerates the development of organic synthesis routes of pharmaceuticals and industrial chemicals. CASP tools are generally developed on the rules or data of synthetic chemistry which include some enzymatic reactions. However, synthetic biology offers a new degree of freedom through the potential to engineer new synthetic steps. In this work, we present a method to hybridise conventional organic synthesis and synthetic biology to guide synthesis planning. A section of organic reactions from Reaxys® database was combined with metabolic reactions from KEGG database as reactions pools. The combined database was used to assemble synthetic pathways from multiple building blocks to a target molecule. The routes assembly was performed using reinforcement learning, which was adapted to learn the values of molecular structures in synthesis planning, and to develop a policy model to suggest near-optimal multi-step synthesis route choices from the available reactions pool. To quantify the added value of synthetic biology in the hybrid routes, three policy model ‘decision makers’ were developed from the organic, biological and hybrid reactions pools respectively. The near-optimal synthetic routes planned from the three reactions pools were evaluated and compared to discuss the benefits of the hybrid synthetic chemistry plus synthetic biology decision space in reaction routes optimisation.