RetroDiff: Retrosynthesis as Multi-stage Distribution Interpolation
This work addresses a key challenge for chemists in drug discovery by improving retrosynthesis prediction, though it is incremental as it builds on existing diffusion models and semi-template workflows.
The paper tackles the retrosynthesis problem in biopharmaceuticals by proposing RetroDiff, a diffusion-based method that decomposes the task into multi-stage distribution interpolation, achieving higher accuracy than semi-template methods and outperforming other approaches in specific scenarios.
Retrosynthesis poses a key challenge in biopharmaceuticals, aiding chemists in finding appropriate reactant molecules for given product molecules. With reactants and products represented as 2D graphs, retrosynthesis constitutes a conditional graph-to-graph (G2G) generative task. Inspired by advancements in discrete diffusion models for graph generation, we aim to design a diffusion-based method to address this problem. However, integrating a diffusion-based G2G framework while retaining essential chemical reaction template information presents a notable challenge. Our key innovation involves a multi-stage diffusion process. We decompose the retrosynthesis procedure to first sample external groups from the dummy distribution given products, then generate external bonds to connect products and generated groups. Interestingly, this generation process mirrors the reverse of the widely adapted semi-template retrosynthesis workflow, \emph{i.e.} from reaction center identification to synthon completion. Based on these designs, we introduce Retrosynthesis Diffusion (RetroDiff), a novel diffusion-based method for the retrosynthesis task. Experimental results demonstrate that RetroDiff surpasses all semi-template methods in accuracy, and outperforms template-based and template-free methods in large-scale scenarios and molecular validity, respectively. Code: https://github.com/Alsace08/RetroDiff.