设计能定向调控蛋白构象转变的别构配体，区分激动剂与拮抗剂。
TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation
- 基于序列生成配体，通过方向性过渡控制实现功能导向设计。
- 在多个GPCR靶点上成功生成具有指定功能的配体，性能优于传统方法。
- 适合药物设计中需精准控制药效方向的场景，如神经精神类药物研发。
蛋白质功能常由配体引导状态转变方向（如激动剂或拮抗剂）来调控，而非仅稳定单一构象。这对临床重要的G蛋白偶联受体（GPCRs）尤为关键，因治疗效果依赖于功能方向性。现有基于结构的设计方法仅优化对静态构象的结合，无法体现非可逆的方向性效应，也难以系统区分激动剂与拮抗剂行为。为此，我们提出面向别构配体设计的过渡导向离散扩散框架TD3B，其通过目标感知的方向性判别器、软结合亲和力门控以及预训练离散扩散模型的快速微调，实现功能导向的配体生成，可独立于结合亲和力设计激动剂或拮抗剂，且传统基于平衡态或仅推理引导的方法无法达到此效果。代码与模型检查点已公开于https://huggingface.co/ChatterjeeLab/TD3B。
原文摘要 · Abstract (English)
Protein function is often controlled by ligands that bias the direction of state transitions, such as agonists and antagonists, rather than stabilizing a single conformation. This is especially important for clinically relevant G protein-coupled receptors (GPCRs), where therapeutic efficacy depends on functional directionality. Structure-based design methods optimize binding to static conformations and cannot represent non-reversible, directional effects or systematically distinguish agonist from antagonist behavior. To address this gap, we introduce Transition-Directed Discrete Diffusion for Allosteric Binder Design (TD3B), a sequence-based generative framework that designs binders with specified agonist or antagonist behavior via a directional transition control objective. TD3B combines a target-aware Direction Oracle, a soft binding-affinity gate, and amortized fine-tuning of a pre-trained discrete diffusion model, enabling targeted agonist and antagonist generation decoupled from binding affinity and unattainable by equilibrium-based or inference-only guidance baselines. The code and checkpoints are available at https://huggingface.co/ChatterjeeLab/TD3B.
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