# FragFM: Hierarchical Framework for Efficient Molecule Generation via Fragment-Level Discrete Flow Matching

arXiv: https://arxiv.org/abs/2502.15805 · HTML: https://mlsanity.com/paper/2502.15805/

## Key facts

- Cited by 7 papers in the map (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 52 of its 88 references that are in the map.
- First posted on arXiv 19 Feb 2025.

## 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 52)

- [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)
- [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)
- [Representation Learning with Contrastive Predictive Coding](https://mlsanity.com/paper/1807.03748/) (2018)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [How Powerful are Graph Neural Networks?](https://mlsanity.com/paper/1810.00826/) (2018)
- [Neural Message Passing for Quantum Chemistry](https://mlsanity.com/paper/1704.01212/) (2017)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Calibrate Before Use: Improving Few-Shot Performance of Language Models](https://mlsanity.com/paper/2102.09690/) (2021)
- [Generating Diverse High-Fidelity Images with VQ-VAE-2](https://mlsanity.com/paper/1906.00446/) (2019)
- [Relational inductive biases, deep learning, and graph networks](https://mlsanity.com/paper/1806.01261/) (2018)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [DiGress: Discrete Denoising diffusion for graph generation](https://mlsanity.com/paper/2209.14734/) (2022)
- [Analyzing and Improving the Training Dynamics of Diffusion Models](https://mlsanity.com/paper/2312.02696/) (2023)
- [Discrete Flow Matching](https://mlsanity.com/paper/2407.15595/) (2024)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [Generative Flows on Discrete State-Spaces: Enabling Multimodal Flows with Applications to Protein Co-Design](https://mlsanity.com/paper/2402.04997/) (2024)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (2018)
- [Score-based Generative Modeling of Graphs via the System of Stochastic Differential Equations](https://mlsanity.com/paper/2202.02514/) (2022)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Permutation Invariant Graph Generation via Score-Based Generative Modeling](https://mlsanity.com/paper/2003.00638/) (2020)
- [Hierarchical Generation of Molecular Graphs using Structural Motifs](https://mlsanity.com/paper/2002.03230/) (2020)
- [Fr'echet ChemNet Distance: A metric for generative models for molecules in drug discovery](https://mlsanity.com/paper/1803.09518/) (2018)
- [GraphDF: A Discrete Flow Model for Molecular Graph Generation](https://mlsanity.com/paper/2102.01189/) (2021)
- [Denoising Diffusion Bridge Models](https://mlsanity.com/paper/2309.16948/) (2023)
- [Diffusion Schr"odinger Bridge Matching](https://mlsanity.com/paper/2303.16852/) (2023)
- [Graph Inductive Biases in Transformers without Message Passing](https://mlsanity.com/paper/2305.17589/) (2023)

## Built on by (most cited first, 7 of 7)

- [Rethinking Diffusion Models with Symmetries through Canonicalization with Applications to Molecular Graph Generation](https://mlsanity.com/paper/2602.15022/) (2026)
- [3D Molecule Generation from Rigid Motifs via SE(3) Flows](https://mlsanity.com/paper/2601.16955/) (2026)
- [NMIRacle: Multi-modal Generative Molecular Elucidation from IR and NMR Spectra](https://mlsanity.com/paper/2512.19733/) (2025)
- [Autoregressive latent diffusion for 3D molecule generation](https://mlsanity.com/paper/2607.09277/) (2026)
- [Beyond Drug Discovery: The Nanotechnology Molecular Optimization (NMO) Benchmark](https://mlsanity.com/paper/2606.30170/) (2026)
- [FragFlex: Fragment-Based Flexible Molecular Generation for Exploring Vast Chemical Space](https://mlsanity.com/paper/2610.15284/) (2026)
- [MIRRA: Fast, High-Fidelity Molecular Generation with Chemistry-Informed Discrete Flow Matching](https://mlsanity.com/paper/2610.17244/) (2026)

## Abstract (arXiv)

We introduce FragFM, a novel hierarchical framework via fragment-level discrete flow matching for efficient molecular graph generation. FragFM generates molecules at the fragment level, leveraging a coarse-to-fine autoencoder to reconstruct details at the atom level. Together with a stochastic fragment bag strategy to effectively handle a large fragment space, our framework enables more efficient, scalable molecular generation. We demonstrate that our fragment-based approach achieves better property control than the atom-based method and additional flexibility through conditioning the fragment bag. We also propose a Natural Product Generation benchmark (NPGen) to evaluate the ability of modern molecular graph generative models to generate natural product-like molecules. Since natural products are biologically prevalidated and differ from typical drug-like molecules, our benchmark provides a more challenging yet meaningful evaluation relevant to drug discovery. We conduct a comparative study of FragFM against various models on diverse molecular generation benchmarks, including NPGen, demonstrating superior performance. The results highlight the potential of fragment-based generative modeling for large-scale, property-aware molecular design, paving the way for more efficient exploration of chemical space.