# TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generation

arXiv: https://arxiv.org/abs/2605.09810 · HTML: https://mlsanity.com/paper/2605.09810/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 15 of its 63 references that are in the map.
- First posted on arXiv 10 May 2026.

## Builds on (most cited first, 15 of 15)

- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Diffusion Posterior Sampling for General Noisy Inverse Problems](https://mlsanity.com/paper/2209.14687/) (2022)
- [Simple and Effective Masked Diffusion Language Models](https://mlsanity.com/paper/2406.07524/) (2024)
- [Discrete Diffusion Modeling by Estimating the Ratios of the Data Distribution](https://mlsanity.com/paper/2310.16834/) (2023)
- [Simplified and Generalized Masked Diffusion for Discrete Data](https://mlsanity.com/paper/2406.04329/) (2024)
- [Practical and Asymptotically Exact Conditional Sampling in Diffusion Models](https://mlsanity.com/paper/2306.17775/) (2023)
- [Unlocking Guidance for Discrete State-Space Diffusion and Flow Models](https://mlsanity.com/paper/2406.01572/) (2024)
- [Fine-Tuning Discrete Diffusion Models via Reward Optimization with Applications to DNA and Protein Design](https://mlsanity.com/paper/2410.13643/) (2024)
- [Particle Denoising Diffusion Sampler](https://mlsanity.com/paper/2402.06320/) (2024)
- [PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion](https://mlsanity.com/paper/2412.17780/) (2024)
- [Multi-Objective-Guided Discrete Flow Matching for Controllable Biological Sequence Design](https://mlsanity.com/paper/2505.07086/) (2025)
- [TR2-D2: Tree Search Guided Trajectory-Aware Fine-Tuning for Discrete Diffusion](https://mlsanity.com/paper/2509.25171/) (2025)
- [AReUReDi: Annealed Rectified Updates for Refining Discrete Flows with Multi-Objective Guidance](https://mlsanity.com/paper/2510.00352/) (2025)

## Built on by (most cited first, 1 of 1)

- [AlloGen: Conformation-Selective Binder Generation with Differential State Scoring](https://mlsanity.com/paper/2606.05474/) (2026)

## Abstract (arXiv)

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.