DFRscore: Deep Learning-Based Scoring of Synthetic Complexity with Drug-Focused Retrosynthetic Analysis for High-Throughput Virtual Screening

Abstract

Recently emerging generative AI models enable us to produce a vast number of compounds for potential applications. While they can provide novel molecular structures, the synthetic feasibility of the generated molecules is often questioned. To address this issue, a few recent studies have attempted to use deep learning models to estimate the synthetic accessibility of many molecules rapidly. However, retrosynthetic analysis tools used to train the models rely on reaction templates automatically extracted from a large reaction database that are not domain-specific and may exhibit low chemical correctness. To overcome this limitation, we introduce DFRscore (Drug-Focused Retrosynthetic score), a deep learning-based approach for a more practical assessment of synthetic accessibility in drug discovery. The DFRscore model is trained exclusively on drug-focused reactions, providing a predicted number of minimally required synthetic steps for each compound. This approach enables practitioners to filter out compounds that do not meet their desired level of synthetic accessibility at an early stage of high-throughput virtual screening for accelerated drug discovery. The proposed strategy can be easily adapted to other domains by adjusting the synthesis planning setup of the reaction templates and starting materials.