Organic Compound Synthetic Accessibility Prediction Based on the Graph Attention Mechanism.

Abstract

Accurate estimation of the synthetic accessibility of small molecules is needed in many phases of drug discovery. Several expert-crafted scoring methods and descriptor-based quantitative structure-activity relationship (QSAR) models have been developed for synthetic accessibility assessment, but their practical applications in drug discovery are still quite limited because of relatively low prediction accuracy and poor model interpretability. In this study, we proposed a data-driven interpretable prediction framework called GASA (Graph Attention-based assessment of Synthetic Accessibility) to evaluate the synthetic accessibility of small molecules by distinguishing compounds to be easy- (ES) or hard-to-synthesize (HS). GASA is a graph neural network (GNN) architecture that makes self-feature deduction by applying an attention mechanism to automatically capture the most important structural features related to synthetic accessibility. The sampling around the hypothetical classification boundary was used to improve the ability of GASA to distinguish structurally similar molecules. GASA was extensively evaluated and compared with two descriptor-based machine learning methods (random forest, RF; eXtreme gradient boosting, XGBoost) and four existing scores (SYBA: SYnthetic Bayesian Accessibility; SCScore: Synthetic Complexity score; RAscore: Retrosynthetic Accessibility score; SAscore: Synthetic Accessibility score). Our analysis demonstrates that GASA achieved remarkable performance in distinguishing similar molecules compared with other methods and had a broader applicability domain. In addition, we show how GASA learns the important features that affect molecular synthetic accessibility by assigning attention weights to different atoms. An online prediction service for GASA was offered at http://cadd.zju.edu.cn/gasa/.