PockLigGPT: Pocket-Sequence-Conditioned Molecular Generation with GPTs and RL

Abstract

De novo drug design aims to generate molecules targeting specific protein pockets while retaining chemical plausibility and drug-like properties. Recent 3D structure-based generative methods explicitly model pocket-ligand geometry, but this does not always translate into chemically realistic or practically usable candidate molecules. Molecular language models provide a complementary sequence-based alternative. However, it remains unclear whether sequence-based pocket information can effectively guide ligand generation, whether multistage training improves pocket-specific generation, and whether docking-guided reinforcement learning can be integrated into a practical generation pipeline. We introduce PockLigGPT, a GPT-based framework for pocket-sequence-conditioned molecular generation. Rather than producing fixed 3D coordinates, PockLigGPT formulates ligand design as a sequence-generation problem conditioned on the amino acid composition of the protein pocket. The model is trained in four stages: large-scale chemical pretraining based on ZINC20; bioactivity-oriented adaptation based on ChEMBL; pocket-sequence-conditioned fine-tuning using binding-pocket amino acid sequences paired with ligands; and, finally, pocket-specific docking-guided reinforcement learning using AutoDock Vina-based rewards. PockLigGPT achieves competitive docking-oriented performance under a standardized evaluation protocol while maintaining chemical plausibility, favorable physicochemical profiles, and Lipinski-based drug-likeness. Docking studies on Alzheimer’s disease-associated targets and token-level analyses further support the utility of PockLigGPT for de novo drug design.