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

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.可合成性对于计算机辅助设计（in silico）的化合物而言至关重要。尽管如此，在化合物的设计与优化流程中，合成可及性往往仅被视为事后补充考量的因素。此外，现代计算机辅助药物设计方法的发展趋势正朝着全自动化方向演进，逐渐丧失了融入用户专业知识的可能性。 本研究推出了我们的软件工具Syntheshesia的第二次正式更新版本，该工具专为兼顾合成性的先导化合物结构修饰而开发，如今可充分利用用户的专业知识。该工具将用户提供的逆合成路线作为引导路径，用于指导对目标化合物实施符合预期的结构修饰。此外，该方法支持用户自定义逆合成路线中需要进行修饰的具体位置或组分，进一步强化了对用户专业知识的整合利用。 本文详细阐述了Syntheshesia的功能、基本概念，以及多种应用场景：从简单示例出发，涵盖不同交换函数的效果对比，再到对一组生物电子等排体连接子结构的分析，着重展示了该工具可筛选出具备合成可行性的潜在替代结构。