# Fine-tuning Pocket-Aware Diffusion Models via Denoising Policy Optimization

arXiv: https://arxiv.org/abs/2605.17693 · HTML: https://mlsanity.com/paper/2605.17693/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 37 of its 45 references that are in the map.
- First posted on arXiv 17 May 2026.

## Placed in

- Diffusion models / [Flow matching, time series and science](https://mlsanity.com/diffusion/flow-matching-time-series-and-science/)

## Builds on (most cited first, 30 of 37)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Proximal Policy Optimization Algorithms](https://mlsanity.com/paper/1707.06347/) (2017)
- [DeepSeekMath: Pushing the Limits of Mathematical Reasoning in Open Language Models](https://mlsanity.com/paper/2402.03300/) (2024)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Direct Preference Optimization: Your Language Model is Secretly a Reward Model](https://mlsanity.com/paper/2305.18290/) (2023)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [An Image is Worth One Word: Personalizing Text-to-Image Generation using Textual Inversion](https://mlsanity.com/paper/2208.01618/) (2022)
- [Variational Diffusion Models](https://mlsanity.com/paper/2107.00630/) (2021)
- [Improved Techniques for Training Score-Based Generative Models](https://mlsanity.com/paper/2006.09011/) (2020)
- [Training Diffusion Models with Reinforcement Learning](https://mlsanity.com/paper/2305.13301/) (2023)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Diffusion Model Alignment Using Direct Preference Optimization](https://mlsanity.com/paper/2311.12908/) (2023)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Compositional Visual Generation with Composable Diffusion Models](https://mlsanity.com/paper/2206.01714/) (2022)
- [DPOK: Reinforcement Learning for Fine-tuning Text-to-Image Diffusion Models](https://mlsanity.com/paper/2305.16381/) (2023)
- [Using Human Feedback to Fine-tune Diffusion Models without Any Reward Model](https://mlsanity.com/paper/2311.13231/) (2023)
- [Reduce, Reuse, Recycle: Compositional Generation with Energy-Based Diffusion Models and MCMC](https://mlsanity.com/paper/2302.11552/) (2023)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction](https://mlsanity.com/paper/2303.03543/) (2023)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design](https://mlsanity.com/paper/2403.07902/) (2024)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)
- [MolCRAFT: Structure-Based Drug Design in Continuous Parameter Space](https://mlsanity.com/paper/2404.12141/) (2024)
- [Reinforced Genetic Algorithm for Structure-based Drug Design](https://mlsanity.com/paper/2211.16508/) (2022)
- [Structure-based drug design with geometric deep learning](https://mlsanity.com/paper/2210.11250/) (2022)
- [Towards Better Alignment: Training Diffusion Models with Reinforcement Learning Against Sparse Rewards](https://mlsanity.com/paper/2503.11240/) (2025)
- [DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization](https://mlsanity.com/paper/2403.13829/) (2024)

## Abstract (arXiv)

Structure-based drug design has been accelerated by pocket-aware 3D generative models, yet most methods primarily fit the training distribution and may fall short of satisfying multiple properties required in real-world therapeutic drug discovery. Recently, increasing attention has focused on structure-based molecule optimization (SBMO), which targets fine-grained control over multiple specified molecular properties. In this paper, we present DEPPA, a novel SBMO approach building upon Denoising Diffusion Policy Optimization for fine-tuning a pre-trained pocket-aware diffusion model via reinforcement learning. DEPPA enables optimization over multiple properties, including binding affinity, drug-likeness, synthesizability and diversity. We formulate the reverse denoising process of the pretrained pocket-aware diffusion model as a multi-step Markov Decision Process, where the desired properties that serve as reward signals are evaluated on the final generated ligand molecules. DEPPA incorporates a coarse denoising scheduler during the RL fine-tuning to achieve efficient and effective molecule optimization. Experimental results on the CrossDocked2020 benchmark demonstrate that DEPPA outperforms baselines in binding affinity (Vina Score -8.5 kcal/mol), drug-likeness and diversity while exhibiting competitive performance in synthesizability. The source code is available at https://github.com/xy9485/DePPA .