Full Modification Control over Retrosynthetic Routes for Guided Optimization of Lead Structures.

Abstract

Synthesizability is essential for compounds designed in silico. Regardless, synthetic accessibility is often considered only as an afterthought in the design and optimization process. In addition, the trend with modern computer-aided drug design methods is going toward full automation and away from the possibility of incorporating user knowledge. With this work, we present the second major release of our software tool, Synthesia, for synthesis-aware lead structure modification, where the user's expertise is now fully utilized. A provided retrosynthetic route is used as a pathway to guide structural modifications that introduce desired structural changes in the target compound. Moreover, the approach allows the user to define the exact position or component in the retrosynthetic route, which should be modified, further integrating the user's expert knowledge. This paper describes the functionality of Synthesia, its basic concepts, and several application scenarios ranging from simple examples to a comparison of the effects of the different exchange functions to an analysis of a set of bioisosteric linker structures, highlighting potential synthetically feasible replacements.