# Prior-Guided Flow Matching for Target-Aware Molecule Design with Learnable Atom Number

arXiv: https://arxiv.org/abs/2509.01486 · HTML: https://mlsanity.com/paper/2509.01486/

## Key facts

- Cited by 6 papers in the map (data through 14 Oct 2026).
- Builds on 29 of its 53 references that are in the map.
- First posted on arXiv 1 Sep 2025.

## Builds on (most cited first, 29 of 29)

- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Improving and generalizing flow-based generative models with minibatch optimal transport](https://mlsanity.com/paper/2302.00482/) (2023)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [Multisample Flow Matching: Straightening Flows with Minibatch Couplings](https://mlsanity.com/paper/2304.14772/) (2023)
- [Equivariant Flows: Exact Likelihood Generative Learning for Symmetric Densities](https://mlsanity.com/paper/2006.02425/) (2020)
- [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)
- [E(n) Equivariant Normalizing Flows](https://mlsanity.com/paper/2105.09016/) (2021)
- [Flow Matching in Latent Space](https://mlsanity.com/paper/2307.08698/) (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)
- [Guided Flows for Generative Modeling and Decision Making](https://mlsanity.com/paper/2311.13443/) (2023)
- [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)
- [Bayesian Flow Networks](https://mlsanity.com/paper/2308.07037/) (2023)
- [Equivariant Flow Matching with Hybrid Probability Transport](https://mlsanity.com/paper/2312.07168/) (2023)
- [MolCRAFT: Structure-Based Drug Design in Continuous Parameter Space](https://mlsanity.com/paper/2404.12141/) (2024)
- [Full-Atom Peptide Design based on Multi-modal Flow Matching](https://mlsanity.com/paper/2406.00735/) (2024)
- [Learning Subpocket Prototypes for Generalizable Structure-based Drug Design](https://mlsanity.com/paper/2305.13997/) (2023)
- [Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization](https://mlsanity.com/paper/2407.01648/) (2024)
- [CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph](https://mlsanity.com/paper/2406.10840/) (2024)
- [Target-aware Molecular Graph Generation](https://mlsanity.com/paper/2202.04829/) (2022)
- [TAGMol: Target-Aware Gradient-guided Molecule Generation](https://mlsanity.com/paper/2406.01650/) (2024)
- [Rectified Flow For Structure Based Drug Design](https://mlsanity.com/paper/2412.01174/) (2024)

## Built on by (most cited first, 6 of 6)

- [ToolMol: Evolutionary Agentic Framework for Multi-objective Drug Discovery](https://mlsanity.com/paper/2605.12784/) (2026)
- [Generative Molecular Morphing for Flexible-Size Design via Unbalanced Optimal Transport](https://mlsanity.com/paper/2606.07239/) (2026)
- [Fused Bayesian Flow Networks for Dual-Target Molecular Design](https://mlsanity.com/paper/2608.01007/) (2026)
- [Language-Informed Flow Matching for Trend-Guided Structure-Based 3D Molecular Generation](https://mlsanity.com/paper/2608.31009/) (2026)
- [PocketVE: Stable and Property-Guided Structure-Based Drug Design with Variance-Exploding Diffusion](https://mlsanity.com/paper/2609.08101/) (2026)
- [A Systematic Evaluation of Molecule Generation Models for De Novo Drug Design: From Benchmarks to Practical Insights](https://mlsanity.com/paper/2609.10099/) (2026)

## Abstract (arXiv)

Structure-based drug design (SBDD), aiming to generate 3D molecules with high binding affinity toward target proteins, is a vital approach in novel drug discovery. Although recent generative models have shown great potential, they suffer from unstable probability dynamics and mismatch between generated molecule size and the protein pockets geometry, resulting in inconsistent quality and off-target effects. We propose PAFlow, a novel target-aware molecular generation model featuring prior interaction guidance and a learnable atom number predictor. PAFlow adopts the efficient flow matching framework to model the generation process and constructs a new form of conditional flow matching for discrete atom types. A protein-ligand interaction predictor is incorporated to guide the vector field toward higher-affinity regions during generation, while an atom number predictor based on protein pocket information is designed to better align generated molecule size with target geometry. Extensive experiments on the CrossDocked2020 benchmark show that PAFlow achieves a new state-of-the-art in binding affinity (up to -8.31 Avg. Vina Score), simultaneously maintains favorable molecular properties.