Synthesis-Aware Generation of Structural Analogues

In modern 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 feasibility
of the target structure is often neglected during this process, resulting
in structures with low or suboptimal synthetic accessibility. 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 synthesizability 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 applicability
of a particular 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 compatibility with the same synthetic pathways,
maximizing the synthetic efficiency and providing an initial estimation
of the effort of synthesizing the entire series. Altogether, we demonstrate
Synthesia’s ability to modify compound properties while maintaining
in silico synthesizability.