# 3D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Prediction

arXiv: https://arxiv.org/abs/2303.03543 · HTML: https://mlsanity.com/paper/2303.03543/

## Key facts

- Cited by 177 papers in the map (data through 14 Oct 2026).
- Builds on 37 of its 68 references that are in the map.
- First posted on arXiv 6 Mar 2023.

## Builds on (most cited first, 30 of 37)

- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [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)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Tensor field networks: Rotation- and translation-equivariant neural networks for 3D point clouds](https://mlsanity.com/paper/1802.08219/) (2018)
- [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)
- [SE(3)-Transformers: 3D Roto-Translation Equivariant Attention Networks](https://mlsanity.com/paper/2006.10503/) (2020)
- [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)
- [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)
- [Grammar Variational Autoencoder](https://mlsanity.com/paper/1703.01925/) (2017)
- [Equivariant Flows: Exact Likelihood Generative Learning for Symmetric Densities](https://mlsanity.com/paper/2006.02425/) (2020)
- [Learning Deep Generative Models of Graphs](https://mlsanity.com/paper/1803.03324/) (2018)
- [Optimization of Molecules via Deep Reinforcement Learning](https://mlsanity.com/paper/1810.08678/) (2018)
- [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)
- [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)
- [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)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)
- [Symmetry-Aware Actor-Critic for 3D Molecular Design](https://mlsanity.com/paper/2011.12747/) (2020)
- [Multi-Scale Representation Learning on Proteins](https://mlsanity.com/paper/2204.02337/) (2022)

## Built on by (most cited first, 30 of 177)

- [Feynman-Kac Correctors in Diffusion: Annealing, Guidance, and Product of Experts](https://mlsanity.com/paper/2503.02819/) (2025)
- [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)
- [Equivariant Diffusion Policy](https://mlsanity.com/paper/2407.01812/) (2024)
- [MolDiff: Addressing the Atom-Bond Inconsistency Problem in 3D Molecule Diffusion Generation](https://mlsanity.com/paper/2305.07508/) (2023)
- [On the Design Fundamentals of Diffusion Models: A Survey](https://mlsanity.com/paper/2306.04542/) (2023)
- [CoCoGen: Physically-Consistent and Conditioned Score-based Generative Models for Forward and Inverse Problems](https://mlsanity.com/paper/2312.10527/) (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)
- [MolCRAFT: Structure-Based Drug Design in Continuous Parameter Space](https://mlsanity.com/paper/2404.12141/) (2024)
- [SemlaFlow -- Efficient 3D Molecular Generation with Latent Attention and Equivariant Flow Matching](https://mlsanity.com/paper/2406.07266/) (2024)
- [3D molecule generation by denoising voxel grids](https://mlsanity.com/paper/2306.07473/) (2023)
- [Functional-Group-Based Diffusion for Pocket-Specific Molecule Generation and Elaboration](https://mlsanity.com/paper/2306.13769/) (2023)
- [A Survey of Generative AI for de novo Drug Design: New Frontiers in Molecule and Protein Generation](https://mlsanity.com/paper/2402.08703/) (2024)
- [Flow matching achieves almost minimax optimal convergence](https://mlsanity.com/paper/2405.20879/) (2024)
- [A Survey of Geometric Graph Neural Networks: Data Structures, Models and Applications](https://mlsanity.com/paper/2403.00485/) (2024)
- [DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization](https://mlsanity.com/paper/2403.13829/) (2024)
- [PPFlow: Target-aware Peptide Design with Torsional Flow Matching](https://mlsanity.com/paper/2405.06642/) (2024)
- [Diffusion Models in textitDe Novo Drug Design](https://mlsanity.com/paper/2406.08511/) (2024)
- [ET-SEED: Efficient Trajectory-Level SE(3) Equivariant Diffusion Policy](https://mlsanity.com/paper/2411.03990/) (2024)
- [Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization](https://mlsanity.com/paper/2407.01648/) (2024)
- [LIDDIA: Language-based Intelligent Drug Discovery Agent](https://mlsanity.com/paper/2502.13959/) (2025)
- [UniGEM: A Unified Approach to Generation and Property Prediction for Molecules](https://mlsanity.com/paper/2410.10516/) (2024)
- [PharmAgents: Building a Virtual Pharma with Large Language Model Agents](https://mlsanity.com/paper/2503.22164/) (2025)
- [FlowMol3: Flow Matching for 3D De Novo Small-Molecule Generation](https://mlsanity.com/paper/2508.12629/) (2025)
- [Generative Flows on Synthetic Pathway for Drug Design](https://mlsanity.com/paper/2410.04542/) (2024)
- [Structure-based drug design by denoising voxel grids](https://mlsanity.com/paper/2405.03961/) (2024)
- [CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph](https://mlsanity.com/paper/2406.10840/) (2024)
- [FLOWR: Flow Matching for Structure-Aware De Novo, Interaction- and Fragment-Based Ligand Generation](https://mlsanity.com/paper/2504.10564/) (2025)
- [Diffusion probabilistic models enhance variational autoencoder for crystal structure generative modeling](https://mlsanity.com/paper/2308.02165/) (2023)

## Abstract (arXiv)

Rich data and powerful machine learning models allow us to design drugs for a specific protein target textitin silico. Recently, the inclusion of 3D structures during targeted drug design shows superior performance to other target-free models as the atomic interaction in the 3D space is explicitly modeled. However, current 3D target-aware models either rely on the voxelized atom densities or the autoregressive sampling process, which are not equivariant to rotation or easily violate geometric constraints resulting in unrealistic structures. In this work, we develop a 3D equivariant diffusion model to solve the above challenges. To achieve target-aware molecule design, our method learns a joint generative process of both continuous atom coordinates and categorical atom types with a SE(3)-equivariant network. Moreover, we show that our model can serve as an unsupervised feature extractor to estimate the binding affinity under proper parameterization, which provides an effective way for drug screening. To evaluate our model, we propose a comprehensive framework to evaluate the quality of sampled molecules from different dimensions. Empirical studies show our model could generate molecules with more realistic 3D structures and better affinities towards the protein targets, and improve binding affinity ranking and prediction without retraining.