# FlowMol3: Flow Matching for 3D De Novo Small-Molecule Generation

arXiv: https://arxiv.org/abs/2508.12629 · HTML: https://mlsanity.com/paper/2508.12629/

## Key facts

- Cited by 21 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 41 of its 51 references that are in the map.
- First posted on arXiv 18 Aug 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 41)

- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Building Normalizing Flows with Stochastic Interpolants](https://mlsanity.com/paper/2209.15571/) (2022)
- [Stochastic Interpolants: A Unifying Framework for Flows and Diffusions](https://mlsanity.com/paper/2303.08797/) (2023)
- [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)
- [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)
- [Analog Bits: Generating Discrete Data using Diffusion Models with Self-Conditioning](https://mlsanity.com/paper/2208.04202/) (2022)
- [Graph Convolutional Policy Network for Goal-Directed Molecular Graph Generation](https://mlsanity.com/paper/1806.02473/) (2018)
- [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)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Constrained Graph Variational Autoencoders for Molecule Design](https://mlsanity.com/paper/1805.09076/) (2018)
- [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)
- [Symmetry-adapted generation of 3d point sets for the targeted discovery of molecules](https://mlsanity.com/paper/1906.00957/) (2019)
- [E(n) Equivariant Normalizing Flows](https://mlsanity.com/paper/2105.09016/) (2021)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Equivariant flow matching](https://mlsanity.com/paper/2306.15030/) (2023)
- [FlowMM: Generating Materials with Riemannian Flow Matching](https://mlsanity.com/paper/2406.04713/) (2024)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Syntax-Directed Variational Autoencoder for Structured Data](https://mlsanity.com/paper/1802.08786/) (2018)
- [MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation](https://mlsanity.com/paper/2302.09048/) (2023)
- [MatterGen: a generative model for inorganic materials design](https://mlsanity.com/paper/2312.03687/) (2023)
- [All-atom Diffusion Transformers: Unified generative modelling of molecules and materials](https://mlsanity.com/paper/2503.03965/) (2025)
- [MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation](https://mlsanity.com/paper/2305.07508/) (2023)
- [Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2404.19739/) (2024)

## Built on by (most cited first, 21 of 21)

- [Efficient Tail-Aware Generative Optimization via Flow Model Fine-Tuning](https://mlsanity.com/paper/2602.16796/) (2026)
- [Zatom-1: Towards a Multimodal Foundation Model for 3D Molecules and Materials](https://mlsanity.com/paper/2602.22251/) (2026)
- [NEAT: Neighborhood-Guided, Efficient, Autoregressive Set Transformer for 3D Molecular Generation](https://mlsanity.com/paper/2512.05844/) (2025)
- [Fast Organic Crystal Structure Prediction with Unit Cell Flow Matching](https://mlsanity.com/paper/2606.03199/) (2026)
- [Predictive Feature Caching for Training-free Acceleration of Molecular Geometry Generation](https://mlsanity.com/paper/2510.04646/) (2025)
- [FlexiFlow: decomposable flow matching for generation of flexible molecular ensemble](https://mlsanity.com/paper/2511.17249/) (2025)
- [Generative Molecular Morphing for Flexible-Size Design via Unbalanced Optimal Transport](https://mlsanity.com/paper/2606.07239/) (2026)
- [Boltzmann-Expected Molecular Design with Decoupled Annealing Flows](https://mlsanity.com/paper/2607.19519/) (2026)
- [Matching the Optimal Denoiser in Point Cloud Diffusion with (Improved) Rotational Alignment](https://mlsanity.com/paper/2510.03335/) (2025)
- [Inference-Time Compute Scaling For Flow Matching](https://mlsanity.com/paper/2510.17786/) (2025)
- [FlashMol: High-Quality Molecule Generation in as Few as Four Steps](https://mlsanity.com/paper/2605.07020/) (2026)
- [Toward Better Geometric Representations for Molecule Generative Models](https://mlsanity.com/paper/2605.07693/) (2026)
- [Diffusion Models at the Drug Discovery Frontier: A Review on Generating Small Molecules versus Therapeutic Peptides](https://mlsanity.com/paper/2511.00209/) (2025)
- [OMTRA: A Multi-Task Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2512.05080/) (2025)
- [Steerable Neural ODEs on Homogeneous Spaces](https://mlsanity.com/paper/2605.11133/) (2026)
- [Diffusion Flow Matching: Dimension-Improved KL Bounds and Wasserstein Guarantees](https://mlsanity.com/paper/2606.16610/) (2026)
- [Sesame: Structure-Aware Molecular Generation via Spatial Density-Map Conditioning](https://mlsanity.com/paper/2606.23856/) (2026)
- [Ensemble-Conditioned Molecular Design](https://mlsanity.com/paper/2609.15077/) (2026)
- [TreeRef-BFN: Equivariance-Free De Novo Molecule Generation based on 2D Topology and Internal 3D Geometry](https://mlsanity.com/paper/2609.32502/) (2026)
- [Fenchel Tilting: Weighted Correction for Efficient Finetuning of Generative Models](https://mlsanity.com/paper/2609.40030/) (2026)
- [LLM-to-Flow Distillation: Teaching Natural Language Goals to Scientific Generators](https://mlsanity.com/paper/2610.17246/) (2026)

## Abstract (arXiv)

A generative model capable of sampling realistic molecules with desired properties could accelerate chemical discovery across a wide range of applications. Toward this goal, significant effort has focused on developing models that jointly sample molecular topology and 3D structure. We present FlowMol3, an open-source, multi-modal flow matching model that advances the state of the art for all-atom, small-molecule generation. Its substantial performance gains over previous FlowMol versions are achieved without changes to the graph neural network architecture or the underlying flow matching formulation. Instead, FlowMol3's improvements arise from three architecture-agnostic techniques that incur negligible computational cost: self-conditioning, fake atoms, and train-time geometry distortion. FlowMol3 achieves nearly 100% molecular validity for drug-like molecules with explicit hydrogens, more accurately reproduces the functional group composition and geometry of its training data, and does so with an order of magnitude fewer learnable parameters than comparable methods. We hypothesize that these techniques mitigate a general pathology affecting transport-based generative models, enabling detection and correction of distribution drift during inference. Our results highlight simple, transferable strategies for improving the stability and quality of diffusion- and flow-based molecular generative models.