NEAT-POCKET: Pocket-Conditioned Autoregressive 3D Molecular Generation with a Neighborhood-Guided Set Transformer

Abstract

AI-driven de novo molecular design offers a promising route to accelerate early-stage drug discovery by generating novel ligands directly within target protein binding pockets. We present NEAT-POCKET, a pocket-conditioned extension of the autoregressive NEAT model for 3D molecular generation. NEAT-POCKET generates molecules atom by atom in protein pocket environments while preserving atom permutation invariance and explicitly modeling hydrogen atoms. Benchmarks on the CrossDocked and SPINDR datasets show that NEAT-POCKET achieves competitive structure-based generation performance while sampling substantially faster than existing baselines. Beyond full-molecule generation, NEAT-POCKET naturally enables pocket-conditioned fragment completion, a task directly relevant to lead optimization and scaffold elaboration. These results position NEAT-POCKET as a fast, flexible, and practical framework for structure-based drug design.