# Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation

arXiv: https://arxiv.org/abs/2309.17296 · HTML: https://mlsanity.com/paper/2309.17296/

## Key facts

- Cited by 50 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 44 of its 62 references that are in the map.
- First posted on arXiv 29 Sep 2023.

## 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 44)

- [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)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Elucidating the Design Space of Diffusion-Based Generative Models](https://mlsanity.com/paper/2206.00364/) (2022)
- [Fast Graph Representation Learning with PyTorch Geometric](https://mlsanity.com/paper/1903.02428/) (2019)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [DiffWave: A Versatile Diffusion Model for Audio Synthesis](https://mlsanity.com/paper/2009.09761/) (2020)
- [Geometric Deep Learning: Grids, Groups, Graphs, Geodesics, and Gauges](https://mlsanity.com/paper/2104.13478/) (2021)
- [Diffusion-LM Improves Controllable Text Generation](https://mlsanity.com/paper/2205.14217/) (2022)
- [E(3)-Equivariant Graph Neural Networks for Data-Efficient and Accurate Interatomic Potentials](https://mlsanity.com/paper/2101.03164/) (2021)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Diffusion Schr"odinger Bridge with Applications to Score-Based Generative Modeling](https://mlsanity.com/paper/2106.01357/) (2021)
- [Argmax Flows and Multinomial Diffusion: Learning Categorical Distributions](https://mlsanity.com/paper/2102.05379/) (2021)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [MACE: Higher Order Equivariant Message Passing Neural Networks for Fast and Accurate Force Fields](https://mlsanity.com/paper/2206.07697/) (2022)
- [Grad-TTS: A Diffusion Probabilistic Model for Text-to-Speech](https://mlsanity.com/paper/2105.06337/) (2021)
- [Equivariant message passing for the prediction of tensorial properties and molecular spectra](https://mlsanity.com/paper/2102.03150/) (2021)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [Understanding Diffusion Objectives as the ELBO with Simple Data Augmentation](https://mlsanity.com/paper/2303.00848/) (2023)
- [Torsional Diffusion for Molecular Conformer Generation](https://mlsanity.com/paper/2206.01729/) (2022)
- [Equivariant Flows: Exact Likelihood Generative Learning for Symmetric Densities](https://mlsanity.com/paper/2006.02425/) (2020)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Riemannian Score-Based Generative Modelling](https://mlsanity.com/paper/2202.02763/) (2022)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)

## Built on by (most cited first, 30 of 50)

- [All-atom Diffusion Transformers: Unified generative modelling of molecules and materials](https://mlsanity.com/paper/2503.03965/) (2025)
- [Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2404.19739/) (2024)
- [SemlaFlow -- Efficient 3D Molecular Generation with Latent Attention and Equivariant Flow Matching](https://mlsanity.com/paper/2406.07266/) (2024)
- [Cometh: A continuous-time discrete-state graph diffusion model](https://mlsanity.com/paper/2406.06449/) (2024)
- [UniGEM: A Unified Approach to Generation and Property Prediction for Molecules](https://mlsanity.com/paper/2410.10516/) (2024)
- [FlowMol3: Flow Matching for 3D De Novo Small-Molecule Generation](https://mlsanity.com/paper/2508.12629/) (2025)
- [FLOWR: Flow Matching for Structure-Aware De Novo, Interaction- and Fragment-Based Ligand Generation](https://mlsanity.com/paper/2504.10564/) (2025)
- [NExT-Mol: 3D Diffusion Meets 1D Language Modeling for 3D Molecule Generation](https://mlsanity.com/paper/2502.12638/) (2025)
- [Geometric Representation Condition Improves Equivariant Molecule Generation](https://mlsanity.com/paper/2410.03655/) (2024)
- [Applications of Modular Co-Design for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2505.18392/) (2025)
- [Equivariant Neural Diffusion for Molecule Generation](https://mlsanity.com/paper/2506.10532/) (2025)
- [Learning Diffusion Models with Flexible Representation Guidance](https://mlsanity.com/paper/2507.08980/) (2025)
- [TABASCO: A Fast, Simplified Model for Molecular Generation with Improved Physical Quality](https://mlsanity.com/paper/2507.00899/) (2025)
- [Exploring Discrete Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2411.16644/) (2024)
- [Controlled Generation with Equivariant Variational Flow Matching](https://mlsanity.com/paper/2506.18340/) (2025)
- [Straight-Line Diffusion Model for Efficient 3D Molecular Generation](https://mlsanity.com/paper/2503.02918/) (2025)
- [GEOM-Drugs Revisited: Toward More Chemically Accurate Benchmarks for 3D Molecule Generation](https://mlsanity.com/paper/2505.00169/) (2025)
- [Rethinking Diffusion Models with Symmetries through Canonicalization with Applications to Molecular Graph Generation](https://mlsanity.com/paper/2602.15022/) (2026)
- [Zero Shot Molecular Generation via Similarity Kernels](https://mlsanity.com/paper/2402.08708/) (2024)
- [Compositional Flows for 3D Molecule and Synthesis Pathway Co-design](https://mlsanity.com/paper/2504.08051/) (2025)
- [General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design](https://mlsanity.com/paper/2406.16821/) (2024)
- [Rao-Blackwell Gradient Estimators for Equivariant Denoising Diffusion](https://mlsanity.com/paper/2502.09890/) (2025)
- [SynCoGen: Synthesizable 3D Molecule Generation via Joint Reaction and Coordinate Modeling](https://mlsanity.com/paper/2507.11818/) (2025)
- [Zatom-1: Towards a Multimodal Foundation Model for 3D Molecules and Materials](https://mlsanity.com/paper/2602.22251/) (2026)
- [Disentangling Total-Variance and Signal-to-Noise-Ratio Improves Diffusion Models](https://mlsanity.com/paper/2502.08598/) (2025)
- [MolGuidance: Advanced Guidance Strategies for Conditional Molecular Generation with Flow Matching](https://mlsanity.com/paper/2512.12198/) (2025)
- [Scalable Non-Equivariant 3D Molecule Generation via Rotational Alignment](https://mlsanity.com/paper/2506.10186/) (2025)
- [Unraveling the Potential of Diffusion Models in Small Molecule Generation](https://mlsanity.com/paper/2507.08005/) (2025)
- [FLOWR.root: A flow matching based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity prediction](https://mlsanity.com/paper/2510.02578/) (2025)
- [From thermodynamics to protein design: Diffusion models for biomolecule generation towards autonomous protein engineering](https://mlsanity.com/paper/2501.02680/) (2025)

## Abstract (arXiv)

Deep generative diffusion models are a promising avenue for 3D de novo molecular design in materials science and drug discovery. However, their utility is still limited by suboptimal performance on large molecular structures and limited training data. To address this gap, we explore the design space of E(3)-equivariant diffusion models, focusing on previously unexplored areas. Our extensive comparative analysis evaluates the interplay between continuous and discrete state spaces. From this investigation, we present the EQGAT-diff model, which consistently outperforms established models for the QM9 and GEOM-Drugs datasets. Significantly, EQGAT-diff takes continuous atom positions, while chemical elements and bond types are categorical and uses time-dependent loss weighting, substantially increasing training convergence, the quality of generated samples, and inference time. We also showcase that including chemically motivated additional features like hybridization states in the diffusion process enhances the validity of generated molecules. To further strengthen the applicability of diffusion models to limited training data, we investigate the transferability of EQGAT-diff trained on the large PubChem3D dataset with implicit hydrogen atoms to target different data distributions. Fine-tuning EQGAT-diff for just a few iterations shows an efficient distribution shift, further improving performance throughout data sets. Finally, we test our model on the Crossdocked data set for structure-based de novo ligand generation, underlining the importance of our findings showing state-of-the-art performance on Vina docking scores.