DeCoDe: Decoupling Binding Position and Molecular Conformation in 3D Ligand Diffusion for Structure-Based Drug Design

Tóm tắt (nguồn: OpenReview · © tác giả)

Recent advances in diffusion models show promise for Structure-Based Drug Design (SBDD), which aims to generate 3D ligand molecules that bind tightly to specific protein targets. This involves jointly optimizing the ligand's 3D conformation and its binding position within the protein pocket. However, existing diffusion-based SBDD methods diffuse conformation and binding position synchronously within a high-dimensional joint space, leading to inefficient exploration and suboptimal generation quality in both aspects. To address this, we propose **DeCoDe**, a novel diffusion framework that **decouples** the diffusion processes of the binding position and molecular conformation. Our key insight is to prioritize the perturbation of the ligand's internal conformation in the early stages of the forward (noising) process, while accelerating the perturbation of its global binding position later. This design guides the reverse (denoising) process to *first coarsely position* the ligand within the pocket before *refining its detailed structure*, mimicking a more efficient, step-wise generation strategy. Extensive experiments on the CrossDocked2020 benchmark show that DeCoDe achieves significantly higher structural fidelity (with an average improvement of 18%), while maintaining competitive binding affinity and overall molecular properties compared to state-of-the-art baselines.

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