General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design
This work addresses the challenge of controlling binding affinity during ligand generation for drug design, representing an incremental advance by enhancing existing diffusion models with guidance strategies.
The paper tackles the problem of generating ligands with strong binding affinity in structure-based drug design by introducing BADGER, a framework that incorporates binding affinity guidance into diffusion models, achieving up to a 60% improvement in ligand-protein binding affinity over prior methods.
Structure-based drug design (SBDD) aims to generate ligands that bind strongly and specifically to target protein pockets. Recent diffusion models have advanced SBDD by capturing the distributions of atomic positions and types, yet they often underemphasize binding affinity control during generation. To address this limitation, we introduce \textbf{\textnormal{\textbf{BADGER}}}, a general \textbf{binding-affinity guidance framework for diffusion models in SBDD}. \textnormal{\textbf{BADGER} }incorporates binding affinity awareness through two complementary strategies: (1) \textit{classifier guidance}, which applies gradient-based affinity signals during sampling in a plug-and-play fashion, and (2) \textit{classifier-free guidance}, which integrates affinity conditioning directly into diffusion model training. Together, these approaches enable controllable ligand generation guided by binding affinity. \textnormal{\textbf{BADGER} } can be added to any diffusion model and achieves up to a \textbf{60\% improvement in ligand--protein binding affinity} of sampled molecules over prior methods. Furthermore, we extend the framework to \textbf{multi-constraint diffusion guidance}, jointly optimizing for binding affinity, drug-likeness (QED), and synthetic accessibility (SA) to design realistic and synthesizable drug candidates.