# AUTODIFF: Autoregressive Diffusion Modeling for Structure-based Drug Design

arXiv: https://arxiv.org/abs/2404.02003 · HTML: https://mlsanity.com/paper/2404.02003/

## Key facts

- Cited by 2 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 31 of its 43 references that are in the map.
- First posted on arXiv 2 Apr 2024.

## 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 31)

- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [GLIDE: Towards Photorealistic Image Generation and Editing with Text-Guided Diffusion Models](https://mlsanity.com/paper/2112.10741/) (2021)
- [Diffusion-LM Improves Controllable Text Generation](https://mlsanity.com/paper/2205.14217/) (2022)
- [Plug-and-Play Diffusion Features for Text-Driven Image-to-Image Translation](https://mlsanity.com/paper/2211.12572/) (2022)
- [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)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [GraphRNN: Generating Realistic Graphs with Deep Auto-regressive Models](https://mlsanity.com/paper/1802.08773/) (2018)
- [Pix2Video: Video Editing using Image Diffusion](https://mlsanity.com/paper/2303.12688/) (2023)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [Torsional Diffusion for Molecular Conformer Generation](https://mlsanity.com/paper/2206.01729/) (2022)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Hierarchical Generation of Molecular Graphs using Structural Motifs](https://mlsanity.com/paper/2002.03230/) (2020)
- [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)
- [A 3D Generative Model for Structure-Based Drug Design](https://mlsanity.com/paper/2203.10446/) (2022)
- [Latent Diffusion for Language Generation](https://mlsanity.com/paper/2212.09462/) (2022)
- [Generating 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2204.09410/) (2022)
- [DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design](https://mlsanity.com/paper/2403.07902/) (2024)
- [Text Generation with Diffusion Language Models: A Pre-training Approach with Continuous Paragraph Denoise](https://mlsanity.com/paper/2212.11685/) (2022)
- [SeqDiffuSeq: Text Diffusion with Encoder-Decoder Transformers](https://mlsanity.com/paper/2212.10325/) (2022)
- [DiffBP: Generative Diffusion of 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2211.11214/) (2022)
- [MIMOSA: Multi-constraint Molecule Sampling for Molecule Optimization](https://mlsanity.com/paper/2010.02318/) (2020)
- [Reinforced Genetic Algorithm for Structure-based Drug Design](https://mlsanity.com/paper/2211.16508/) (2022)
- [EmoDiff: Intensity Controllable Emotional Text-to-Speech with Soft-Label Guidance](https://mlsanity.com/paper/2211.09496/) (2022)
- [Molecular Generation with Recurrent Neural Networks (RNNs)](https://mlsanity.com/paper/1705.04612/) (2017)
- [Full-band General Audio Synthesis with Score-based Diffusion](https://mlsanity.com/paper/2210.14661/) (2022)
- [Learning Subpocket Prototypes for Generalizable Structure-based Drug Design](https://mlsanity.com/paper/2305.13997/) (2023)

## Built on by (most cited first, 2 of 2)

- [Compositional Flows for 3D Molecule and Synthesis Pathway Co-design](https://mlsanity.com/paper/2504.08051/) (2025)
- [Unraveling the Potential of Diffusion Models in Small Molecule Generation](https://mlsanity.com/paper/2507.08005/) (2025)

## Abstract (arXiv)

Structure-based drug design (SBDD), which aims to generate molecules that can bind tightly to the target protein, is an essential problem in drug discovery, and previous approaches have achieved initial success. However, most existing methods still suffer from invalid local structure or unrealistic conformation issues, which are mainly due to the poor leaning of bond angles or torsional angles. To alleviate these problems, we propose AUTODIFF, a diffusion-based fragment-wise autoregressive generation model. Specifically, we design a novel molecule assembly strategy named conformal motif that preserves the conformation of local structures of molecules first, then we encode the interaction of the protein-ligand complex with an SE(3)-equivariant convolutional network and generate molecules motif-by-motif with diffusion modeling. In addition, we also improve the evaluation framework of SBDD by constraining the molecular weights of the generated molecules in the same range, together with some new metrics, which make the evaluation more fair and practical. Extensive experiments on CrossDocked2020 demonstrate that our approach outperforms the existing models in generating realistic molecules with valid structures and conformations while maintaining high binding affinity.