# Autoregressive fragment-based diffusion for pocket-aware ligand design

arXiv: https://arxiv.org/abs/2401.05370 · HTML: https://mlsanity.com/paper/2401.05370/

## Key facts

- Cited by 7 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 19 of its 30 references that are in the map.
- First posted on arXiv 15 Dec 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, 19 of 19)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Layer Normalization](https://mlsanity.com/paper/1607.06450/) (2016)
- [Variational Diffusion Models](https://mlsanity.com/paper/2107.00630/) (2021)
- [Geometric deep learning: going beyond Euclidean data](https://mlsanity.com/paper/1611.08097/) (2016)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [Learning from Protein Structure with Geometric Vector Perceptrons](https://mlsanity.com/paper/2009.01411/) (2020)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Autoregressive Diffusion Models](https://mlsanity.com/paper/2110.02037/) (2021)
- [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)
- [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-Ligand Scoring with Convolutional Neural Networks](https://mlsanity.com/paper/1612.02751/) (2016)
- [Learning to design drug-like molecules in three-dimensional space using deep generative models](https://mlsanity.com/paper/2104.08474/) (2021)
- [Structure-aware generation of drug-like molecules](https://mlsanity.com/paper/2111.04107/) (2021)

## Built on by (most cited first, 7 of 7)

- [Diffusion Models in textitDe Novo Drug Design](https://mlsanity.com/paper/2406.08511/) (2024)
- [TAGMol: Target-Aware Gradient-guided Molecule Generation](https://mlsanity.com/paper/2406.01650/) (2024)
- [Compositional Flows for 3D Molecule and Synthesis Pathway Co-design](https://mlsanity.com/paper/2504.08051/) (2025)
- [NEBULA: Neural Empirical Bayes Under Latent Representations for Efficient and Controllable Design of Molecular Libraries](https://mlsanity.com/paper/2407.03428/) (2024)
- [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)
- [HybridLinker: Topology-Guided Posterior Sampling for Enhanced Diversity and Validity in 3D Molecular Linker Generation](https://mlsanity.com/paper/2502.17349/) (2025)

## Abstract (arXiv)

In this work, we introduce AutoFragDiff, a fragment-based autoregressive diffusion model for generating 3D molecular structures conditioned on target protein structures. We employ geometric vector perceptrons to predict atom types and spatial coordinates of new molecular fragments conditioned on molecular scaffolds and protein pockets. Our approach improves the local geometry of the resulting 3D molecules while maintaining high predicted binding affinity to protein targets. The model can also perform scaffold extension from user-provided starting molecular scaffold.