DRlinker: Deep Reinforcement Learning for Optimization in Fragment Linking Design.

Abstract

Fragment-based drug discovery is a widely used strategy for drug design in both academic and pharmaceutical industries. Although fragments can be linked to generate candidate compounds by the latest deep generative models, generating linkers with specified attributes remains underdeveloped. In this study, we presented a novel framework, DRlinker, to control fragment linking toward compounds with given attributes through reinforcement learning. The method has been shown to be effective for many tasks from controlling the linker length and log P, optimizing predicted bioactivity of compounds, to various multiobjective tasks. Specifically, our model successfully generated 91.0% and 93.9% of compounds complying with the desired linker length and log P and improved the 7.5 pChEMBL value in bioactivity optimization. Finally, a quasi-scaffold-hopping study revealed that DRlinker could generate nearly 30% molecules with high 3D similarity but low 2D similarity to the lead inhibitor, demonstrating the benefits and applicability of DRlinker in actual fragment-based drug design.