FlexSBDD: Structure-Based Drug Design with Flexible Protein Modeling

Structure-based drug design (SBDD), which aims to generate 3D ligand molecules binding to target proteins, is a fundamental task in drug discovery. Existing SBDD methods typically treat protein as rigid and neglect protein structural change when binding with ligand molecules, leading to a big gap with real-world scenarios and inferior generation qualities (e.g., many steric clashes). To bridge the gap, we propose FlexSBDD, a deep generative model capable of accurately modeling the flexible protein-ligand complex structure for ligand molecule generation. FlexSBDD adopts an efficient flow matching framework and leverages E(3)-equivariant network with scalar-vector dual representation to model dynamic structural changes. Moreover, novel data augmentation schemes based on structure relaxation/sidechain repacking are adopted to boost performance.