FragDockRL: A Reinforcement Learning Framework for Fragment-Based Ligand Design via Building Block Assembly and Tethered Docking

We propose FragDockRL, a novel molecular design framework that combines building block-based virtual synthesis reactions with reinforcement learning. The method aims to efficiently generate synthesizable molecules by using docking scores as rewards without relying on large molecular databases. Experiments on three targets, VGFR2, FA10, and CSF1R, demonstrate a consistent improvement in the average docking scores of generated molecules as learning progresses. FragDockRL enables molecule generation reflecting realistic synthetic routes, effectively reduces the search space while maintaining chemical diversity, and improves pose prediction accuracy in the tethered docking process by leveraging core structures and 3D coordinate information. Although limitations such as core structure duplication and constraints in fine structural optimization remain, future work will address these issues through improved reaction selection algorithms and multi-objective optimization strategies. FragDockRL offers a molecular design platform that simultaneously considers synthetic feasibility and binding affinity, contributing to efficient hit generation in fragment-based drug discovery.