Synthesis-Aware Generation of Structural Analogues

In moder n drug design, one of the main issues is the optimization of an initial lead structure toward a drug candidate by modifying specific properties in the desired direction. The synthetic feasibi l i t y of the target structure is often neglected during this process, resulting in structures with low or suboptimal synthetic accessibi l i t y . In this work, we present a novel approach for synthesis-aware lead optimization called Synthesia. In contrast to the traditional approaches, Synthesia integrates the preservation of the synthesiz-ability of the target structure into the lead structure modification process. Synthesia is able to create structural diversity for a lead structure that matches user-defined molecular properties without losing the applicabi l i t y of a particula r synthetic pathway. The methodology is validated by demonstrating that Synthesia is capable of providing structural analogues of DrugBank compounds that meet generic modification goals and maintain their synthetic pathways. In addition, Synthesia is used to cluster compounds from two different patent structure series (CDK7, Daurismo) according to their compatibi l i t y with the same synthetic pathw a y s , maximizing the synthetic efficiency and providing an initial estimation of the effort of synthesizing the entire series. Altogether, we demonstrate Synthesias abi l i t y to modify compound properties while maintaining in silico synthesizabi l i t y .