# Structure-based Drug Design with Equivariant Diffusion Models

arXiv: https://arxiv.org/abs/2210.13695 · HTML: https://mlsanity.com/paper/2210.13695/

## Key facts

- Cited by 217 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 34 of its 109 references that are in the map.
- First posted on arXiv 24 Oct 2022.

## 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 34)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [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)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [Neural Message Passing for Quantum Chemistry](https://mlsanity.com/paper/1704.01212/) (2017)
- [Video Diffusion Models](https://mlsanity.com/paper/2204.03458/) (2022)
- [RePaint: Inpainting using Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2201.09865/) (2022)
- [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)
- [Variational Diffusion Models](https://mlsanity.com/paper/2107.00630/) (2021)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Convolutional Networks on Graphs for Learning Molecular Fingerprints](https://mlsanity.com/paper/1509.09292/) (2015)
- [Diffusion Probabilistic Models for 3D Point Cloud Generation](https://mlsanity.com/paper/2103.01458/) (2021)
- [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)
- [Directional Message Passing for Molecular Graphs](https://mlsanity.com/paper/2003.03123/) (2020)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [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)
- [Diffusion probabilistic modeling of protein backbones in 3D for the motif-scaffolding problem](https://mlsanity.com/paper/2206.04119/) (2022)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [EquiBind: Geometric Deep Learning for Drug Binding Structure Prediction](https://mlsanity.com/paper/2202.05146/) (2022)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (2022)
- [Geometric Deep Learning on Molecular Representations](https://mlsanity.com/paper/2107.12375/) (2021)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Protein Structure and Sequence Generation with Equivariant Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2205.15019/) (2022)
- [SE(3) Equivariant Graph Neural Networks with Complete Local Frames](https://mlsanity.com/paper/2110.14811/) (2021)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)

## Built on by (most cited first, 30 of 217)

- [Training Diffusion Models with Reinforcement Learning](https://mlsanity.com/paper/2305.13301/) (2023)
- [DiffusionDet: Diffusion Model for Object Detection](https://mlsanity.com/paper/2211.09788/) (2022)
- [DDP: Diffusion Model for Dense Visual Prediction](https://mlsanity.com/paper/2303.17559/) (2023)
- [Stochastic interpolants with data-dependent couplings](https://mlsanity.com/paper/2310.03725/) (2023)
- [MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation](https://mlsanity.com/paper/2302.09048/) (2023)
- [DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design](https://mlsanity.com/paper/2403.07902/) (2024)
- [EquiBot: SIM(3)-Equivariant Diffusion Policy for Generalizable and Data Efficient Learning](https://mlsanity.com/paper/2407.01479/) (2024)
- [All-atom Diffusion Transformers: Unified generative modelling of molecules and materials](https://mlsanity.com/paper/2503.03965/) (2025)
- [Restoration-Degradation Beyond Linear Diffusions: A Non-Asymptotic Analysis For DDIM-Type Samplers](https://mlsanity.com/paper/2303.03384/) (2023)
- [An Overview of Diffusion Models: Applications, Guided Generation, Statistical Rates and Optimization](https://mlsanity.com/paper/2404.07771/) (2024)
- [A Hitchhiker's Guide to Geometric GNNs for 3D Atomic Systems](https://mlsanity.com/paper/2312.07511/) (2023)
- [A Survey on Diffusion Models for Time Series and Spatio-Temporal Data](https://mlsanity.com/paper/2404.18886/) (2024)
- [MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation](https://mlsanity.com/paper/2305.07508/) (2023)
- [EigenFold: Generative Protein Structure Prediction with Diffusion Models](https://mlsanity.com/paper/2304.02198/) (2023)
- [Unveil Conditional Diffusion Models with Classifier-free Guidance: A Sharp Statistical Theory](https://mlsanity.com/paper/2403.11968/) (2024)
- [Efficient Evolutionary Search Over Chemical Space with Large Language Models](https://mlsanity.com/paper/2406.16976/) (2024)
- [Consistent Diffusion Models: Mitigating Sampling Drift by Learning to be Consistent](https://mlsanity.com/paper/2302.09057/) (2023)
- [Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation](https://mlsanity.com/paper/2404.19739/) (2024)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [A new perspective on building efficient and expressive 3D equivariant graph neural networks](https://mlsanity.com/paper/2304.04757/) (2023)
- [Closed-Form Diffusion Models](https://mlsanity.com/paper/2310.12395/) (2023)
- [SemlaFlow -- Efficient 3D Molecular Generation with Latent Attention and Equivariant Flow Matching](https://mlsanity.com/paper/2406.07266/) (2024)
- [Efficient Diffusion Models: A Comprehensive Survey from Principles to Practices](https://mlsanity.com/paper/2410.11795/) (2024)
- [GSURE-Based Diffusion Model Training with Corrupted Data](https://mlsanity.com/paper/2305.13128/) (2023)
- [3D molecule generation by denoising voxel grids](https://mlsanity.com/paper/2306.07473/) (2023)
- [RetroBridge: Modeling Retrosynthesis with Markov Bridges](https://mlsanity.com/paper/2308.16212/) (2023)
- [A Survey on Graph Diffusion Models: Generative AI in Science for Molecule, Protein and Material](https://mlsanity.com/paper/2304.01565/) (2023)
- [DiffuseBot: Breeding Soft Robots With Physics-Augmented Generative Diffusion Models](https://mlsanity.com/paper/2311.17053/) (2023)
- [Accurate transition state generation with an object-aware equivariant elementary reaction diffusion model](https://mlsanity.com/paper/2304.06174/) (2023)
- [Functional-Group-Based Diffusion for Pocket-Specific Molecule Generation and Elaboration](https://mlsanity.com/paper/2306.13769/) (2023)

## Abstract (arXiv)

Structure-based drug design (SBDD) aims to design small-molecule ligands that bind with high affinity and specificity to pre-determined protein targets. Generative SBDD methods leverage structural data of drugs in complex with their protein targets to propose new drug candidates. These approaches typically place one atom at a time in an autoregressive fashion using the binding pocket as well as previously added ligand atoms as context in each step. Recently a surge of diffusion generative models has entered this domain which hold promise to capture the statistical properties of natural ligands more faithfully. However, most existing methods focus exclusively on bottom-up de novo design of compounds or tackle other drug development challenges with task-specific models. The latter requires curation of suitable datasets, careful engineering of the models and retraining from scratch for each task. Here we show how a single pre-trained diffusion model can be applied to a broader range of problems, such as off-the-shelf property optimization, explicit negative design, and partial molecular design with inpainting. We formulate SBDD as a 3D-conditional generation problem and present DiffSBDD, an SE(3)-equivariant diffusion model that generates novel ligands conditioned on protein pockets. Our in silico experiments demonstrate that DiffSBDD captures the statistics of the ground truth data effectively. Furthermore, we show how additional constraints can be used to improve the generated drug candidates according to a variety of computational metrics. These results support the assumption that diffusion models represent the complex distribution of structural data more accurately than previous methods, and are able to incorporate additional design objectives and constraints changing nothing but the sampling strategy.