FuseDiff能同时生成匹配两个靶点的药物构象,提升多靶点药物设计效率。
FuseDiff: Symmetry-Preserving Joint Diffusion for Dual-Target Structure-Based Drug Design
- 采用端到端扩散模型,联合生成分子图与双靶点结合构象。
- 在共享分子骨架下保持两靶点几何差异性,精度优于现有方法。
- 适用于需协同作用的药物研发,如抗耐药治疗场景。
双靶点结构药物设计旨在生成一个配体及其对应两个靶点口袋的特异性结合构象,实现多靶点治疗以增强疗效并减少耐药性。现有方法多采用分步流程,或通过条件独立假设解耦两个构象,或施加过强相关性,无法实现真正意义上的联合生成。为此,我们提出FuseDiff,一种端到端扩散模型,可同时基于两个靶点口袋生成分子图及双靶点结合构象。FuseDiff采用消息传递骨干网络与双靶点局部上下文融合(DLCF)机制,融合每个原子在两个口袋中的局部信息,支持高效联合建模并保留对称性。结合显式键生成策略,确保在共享分子图下拓扑一致性的同时,允许各口袋内进行靶点特异性的几何适应。为支持规范训练与评估,我们构建了双靶点训练集,并使用独立留出测试集进行验证。在基准数据集和真实双靶点系统上的实验表明,FuseDiff达到当前最优对接性能,并首次实现了对接前对双靶点构象质量的系统性评估。
原文摘要 · Abstract (English)
Dual-target structure-based drug design aims to generate a single ligand together with two pocket-specific binding poses, each compatible with a corresponding target pocket, enabling polypharmacological therapies with improved efficacy and reduced resistance. Existing approaches typically rely on staged pipelines, which either decouple the two poses via conditional-independence assumptions or enforce overly rigid correlations, and therefore fail to jointly generate two target-specific binding modes. To address this, we propose FuseDiff, an end-to-end diffusion model that jointly generates a ligand molecular graph and two pocket-specific binding poses conditioned on both pockets. FuseDiff features a message-passing backbone with Dual-target Local Context Fusion (DLCF), which fuses each ligand atom's local context from both pockets to enable expressive joint modeling while preserving the desired symmetries. Together with explicit bond generation, FuseDiff enforces topological consistency across the two poses under a shared graph while allowing target-specific geometric adaptation in each pocket. To support principled training and evaluation, we derive a dual-target training set and use an independent held-out test set for evaluation. Experiments on the benchmark and a real-world dual-target system show that FuseDiff achieves state-of-the-art docking performance and enables the first systematic assessment of dual-target pose quality prior to docking-based pose search.
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