RetroSynX: A retrosynthetic analysis framework using hybrid reaction templates and group contribution-based thermodynamic models

Organic synthesis plays an essential role in the pharmaceutical industry. The drug synthesis route design is a critical decision step to convert raw materials to drug products. Traditionally, knowledge-based methods are commonly used for the design of the synthesis route. However, this type of method is expensive and time-consuming, which hinders the high-throughput design of the synthesis route. In this article, a retrosynthetic analysis framework is established based on hybird reaction templates and Group Contribution (GC)-based thermodynamic models. First, a hybrid database consisting of partial atom-mapping and full atom-mapping reaction templates is constructed utilizing well-studied organic reactions from literature. Second, numerous virtual reactions are generated from reaction templates with respect to the target molecule, and reaction thermodynamic models based on the GC method are developed to validate the effectiveness of those virtual reactions in a timely fashion. Finally, Breadth-First Search (BFS) algorithm is employed to search candidate retrosynthesis pathways which are thermodynamically feasible. In this procedure, five evaluation criteria are used to identify the top-ranked retrosynthesis pathways through evaluating and optimizing the candidate retrosynthesis pathways, including Fathead Minnow 96-hr LC50 (LC50FM), flash point (Fp), Natural Product-likeness Score (NPScore), Synthesis Accessibility Score (SAScore), and Synthesis Complexity Score (SCScore). A retrosynthetic analysis tool called “RetroSynX” is developed using the proposed framework. With the help of the developed framework and tool, synthesis routes considering thermodynamic feasibility can be obtained. Three case studies involving Aspirin, Ibuprofen and ZatoSetron are presented to highlight the feasibility and reliability of the proposed framework.