# Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design

arXiv: https://arxiv.org/abs/2210.05274 · HTML: https://mlsanity.com/paper/2210.05274/

## Key facts

- Cited by 122 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 22 of its 95 references that are in the map.
- First posted on arXiv 11 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, 22 of 22)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (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)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [RePaint: Inpainting using Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2201.09865/) (2022)
- [Variational Diffusion Models](https://mlsanity.com/paper/2107.00630/) (2021)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Argmax Flows and Multinomial Diffusion: Learning Categorical Distributions](https://mlsanity.com/paper/2102.05379/) (2021)
- [DiGress: Discrete Denoising diffusion for graph generation](https://mlsanity.com/paper/2209.14734/) (2022)
- [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)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Diffusion probabilistic modeling of protein backbones in 3D for the motif-scaffolding problem](https://mlsanity.com/paper/2206.04119/) (2022)
- [E(n) Equivariant Normalizing Flows](https://mlsanity.com/paper/2105.09016/) (2021)
- [Learning Gradient Fields for Molecular Conformation Generation](https://mlsanity.com/paper/2105.03902/) (2021)
- [Provably Strict Generalisation Benefit for Equivariant Models](https://mlsanity.com/paper/2102.10333/) (2021)
- [Learning Neural Generative Dynamics for Molecular Conformation Generation](https://mlsanity.com/paper/2102.10240/) (2021)
- [An End-to-End Framework for Molecular Conformation Generation via Bilevel Programming](https://mlsanity.com/paper/2105.07246/) (2021)
- [3DLinker: An E(3) Equivariant Variational Autoencoder for Molecular Linker Design](https://mlsanity.com/paper/2205.07309/) (2022)
- [Improving the Sample-Complexity of Deep Classification Networks with Invariant Integration](https://mlsanity.com/paper/2202.03967/) (2022)

## Built on by (most cited first, 30 of 122)

- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [SE(3)-Stochastic Flow Matching for Protein Backbone Generation](https://mlsanity.com/paper/2310.02391/) (2023)
- [Iterated Denoising Energy Matching for Sampling from Boltzmann Densities](https://mlsanity.com/paper/2402.06121/) (2024)
- [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)
- [Generative Diffusion Models on Graphs: Methods and Applications](https://mlsanity.com/paper/2302.02591/) (2023)
- [EquiBot: SIM(3)-Equivariant Diffusion Policy for Generalizable and Data Efficient Learning](https://mlsanity.com/paper/2407.01479/) (2024)
- [Two for One: Diffusion Models and Force Fields for Coarse-Grained Molecular Dynamics](https://mlsanity.com/paper/2302.00600/) (2023)
- [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)
- [Feedback Efficient Online Fine-Tuning of Diffusion Models](https://mlsanity.com/paper/2402.16359/) (2024)
- [Position: Graph Learning Will Lose Relevance Due To Poor Benchmarks](https://mlsanity.com/paper/2502.14546/) (2025)
- [Does equivariance matter at scale?](https://mlsanity.com/paper/2410.23179/) (2024)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [Structure-based drug design with geometric deep learning](https://mlsanity.com/paper/2210.11250/) (2022)
- [3D molecule generation by denoising voxel grids](https://mlsanity.com/paper/2306.07473/) (2023)
- [Interpretable Diffusion via Information Decomposition](https://mlsanity.com/paper/2310.07972/) (2023)
- [EDGI: Equivariant Diffusion for Planning with Embodied Agents](https://mlsanity.com/paper/2303.12410/) (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)
- [Trans-Dimensional Generative Modeling via Jump Diffusion Models](https://mlsanity.com/paper/2305.16261/) (2023)
- [A Closer Look at Time Steps is Worthy of Triple Speed-Up for Diffusion Model Training](https://mlsanity.com/paper/2405.17403/) (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)
- [SynFlowNet: Design of Diverse and Novel Molecules with Synthesis Constraints](https://mlsanity.com/paper/2405.01155/) (2024)
- [Diffusion Models in textitDe Novo Drug Design](https://mlsanity.com/paper/2406.08511/) (2024)
- [Bootstrapped Training of Score-Conditioned Generator for Offline Design of Biological Sequences](https://mlsanity.com/paper/2306.03111/) (2023)
- [End-To-End Latent Variational Diffusion Models for Inverse Problems in High Energy Physics](https://mlsanity.com/paper/2305.10399/) (2023)
- [Action-Minimization Meets Generative Modeling: Efficient Transition Path Sampling with the Onsager-Machlup Functional](https://mlsanity.com/paper/2504.18506/) (2025)
- [CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph](https://mlsanity.com/paper/2406.10840/) (2024)

## Abstract (arXiv)

Fragment-based drug discovery has been an effective paradigm in early-stage drug development. An open challenge in this area is designing linkers between disconnected molecular fragments of interest to obtain chemically-relevant candidate drug molecules. In this work, we propose DiffLinker, an E(3)-equivariant 3D-conditional diffusion model for molecular linker design. Given a set of disconnected fragments, our model places missing atoms in between and designs a molecule incorporating all the initial fragments. Unlike previous approaches that are only able to connect pairs of molecular fragments, our method can link an arbitrary number of fragments. Additionally, the model automatically determines the number of atoms in the linker and its attachment points to the input fragments. We demonstrate that DiffLinker outperforms other methods on the standard datasets generating more diverse and synthetically-accessible molecules. Besides, we experimentally test our method in real-world applications, showing that it can successfully generate valid linkers conditioned on target protein pockets.