# Constrained Flow Optimization via Sequential Fine Tuning for Molecular Design

arXiv: https://arxiv.org/abs/2605.30610 · HTML: https://mlsanity.com/paper/2605.30610/

## Key facts

- Cited by 3 papers in the map (data through 14 Oct 2026).
- Builds on 40 of its 61 references that are in the map.
- First posted on arXiv 28 May 2026.

## Builds on (most cited first, 30 of 40)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Denoising Diffusion Implicit Models](https://mlsanity.com/paper/2010.02502/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [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)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Flow-GRPO: Training Flow Matching Models via Online RL](https://mlsanity.com/paper/2505.05470/) (2025)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Adjoint Matching: Fine-tuning Flow and Diffusion Generative Models with Memoryless Stochastic Optimal Control](https://mlsanity.com/paper/2409.08861/) (2024)
- [DiffusionNFT: Online Diffusion Reinforcement with Forward Process](https://mlsanity.com/paper/2509.16117/) (2025)
- [Fine-Tuning of Continuous-Time Diffusion Models as Entropy-Regularized Control](https://mlsanity.com/paper/2402.15194/) (2024)
- [Protein structure generation via folding diffusion](https://mlsanity.com/paper/2209.15611/) (2022)
- [Dirichlet Flow Matching with Applications to DNA Sequence Design](https://mlsanity.com/paper/2402.05841/) (2024)
- [Understanding Reinforcement Learning-Based Fine-Tuning of Diffusion Models: A Tutorial and Review](https://mlsanity.com/paper/2407.13734/) (2024)
- [Fine-Tuning Discrete Diffusion Models via Reward Optimization with Applications to DNA and Protein Design](https://mlsanity.com/paper/2410.13643/) (2024)
- [Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2404.19739/) (2024)
- [Feedback Efficient Online Fine-Tuning of Diffusion Models](https://mlsanity.com/paper/2402.16359/) (2024)
- [Fine-tuning of diffusion models via stochastic control: entropy regularization and beyond](https://mlsanity.com/paper/2403.06279/) (2024)
- [Fine-Tuning Discrete Diffusion Models with Policy Gradient Methods](https://mlsanity.com/paper/2502.01384/) (2025)
- [Diffusion Models as Constrained Samplers for Optimization with Unknown Constraints](https://mlsanity.com/paper/2402.18012/) (2024)
- [Score as Action: Fine-Tuning Diffusion Generative Models by Continuous-time Reinforcement Learning](https://mlsanity.com/paper/2502.01819/) (2025)
- [Diffusion Model for Data-Driven Black-Box Optimization](https://mlsanity.com/paper/2403.13219/) (2024)
- [Efficient Exploration in Continuous-time Model-based Reinforcement Learning](https://mlsanity.com/paper/2310.19848/) (2023)
- [Constrained Diffusion Models via Dual Training](https://mlsanity.com/paper/2408.15094/) (2024)
- [Flow Density Control: Generative Optimization Beyond Entropy-Regularized Fine-Tuning](https://mlsanity.com/paper/2511.22640/) (2025)
- [Provable Maximum Entropy Manifold Exploration via Diffusion Models](https://mlsanity.com/paper/2506.15385/) (2025)
- [Constraint-Aware Diffusion Guidance for Robotics: Real-Time Obstacle Avoidance for Autonomous Racing](https://mlsanity.com/paper/2505.13131/) (2025)

## Built on by (most cited first, 3 of 3)

- [Tilted Schr"odinger Bridge Matching](https://mlsanity.com/paper/2609.34642/) (2026)
- [Manifold Diffusion for Structure Generation of Transition Metal Complexes](https://mlsanity.com/paper/2606.00666/) (2026)
- [LLM-to-Flow Distillation: Teaching Natural Language Goals to Scientific Generators](https://mlsanity.com/paper/2610.17246/) (2026)

## Abstract (arXiv)

Adapting generative foundation models, in particular diffusion and flow models, to optimize given reward functions (e.g., binding affinity) while satisfying constraints (e.g., molecular synthesizability) is fundamental for their adoption in real-world scientific discovery applications such as molecular design or protein engineering. While recent works have introduced scalable methods for reward-guided fine-tuning of such models via reinforcement learning and control schemes, it remains an open problem how to algorithmically trade-off reward maximization and constraint satisfaction in a reliable and predictable manner. Motivated by this challenge, we first present a rigorous framework for Constrained Generative Optimization, which brings an optimization viewpoint to the introduced adaptation problem and retrieves the relevant task of constrained generation as a sub-case. Then, we introduce Constrained Flow Optimization (CFO), an algorithm that automatically and provably balances reward maximization and constraint satisfaction by reducing the original problem to sequential fine-tuning via established, scalable methods. We provide convergence guarantees for constrained generative optimization and constrained generation via CFO. Ultimately, we present an experimental evaluation of CFO on both synthetic, yet illustrative, settings, and a molecular design task. Across these evaluations, CFO achieves consistent increases in reward while ensuring high constraint satisfaction, showcasing its practical utility for constrained generative optimization.