# READ: A Retrieval-Alignment Diffusion Framework for Structure-based Drug Design

arXiv: https://arxiv.org/abs/2506.14488 · HTML: https://mlsanity.com/paper/2506.14488/

## Key facts

- Cited by 1 papers in the map (data through 14 Oct 2026).
- Builds on 22 of its 45 references that are in the map.
- First posted on arXiv 17 Jun 2025.

## Builds on (most cited first, 22 of 22)

- [Retrieval-Augmented Generation for Knowledge-Intensive NLP Tasks](https://mlsanity.com/paper/2005.11401/) (2020)
- [Flamingo: a Visual Language Model for Few-Shot Learning](https://mlsanity.com/paper/2204.14198/) (2022)
- [From Local to Global: A Graph RAG Approach to Query-Focused Summarization](https://mlsanity.com/paper/2404.16130/) (2024)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [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)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (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)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)
- [DiffBP: Generative Diffusion of 3D Molecules for Target Protein Binding](https://mlsanity.com/paper/2211.11214/) (2022)
- [ET-Flow: Equivariant Flow-Matching for Molecular Conformer Generation](https://mlsanity.com/paper/2410.22388/) (2024)
- [Functional-Group-Based Diffusion for Pocket-Specific Molecule Generation and Elaboration](https://mlsanity.com/paper/2306.13769/) (2023)
- [Diffusion Models in textitDe Novo Drug Design](https://mlsanity.com/paper/2406.08511/) (2024)
- [Learning Subpocket Prototypes for Generalizable Structure-based Drug Design](https://mlsanity.com/paper/2305.13997/) (2023)
- [CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph](https://mlsanity.com/paper/2406.10840/) (2024)
- [Generation of 3D Molecules in Pockets via Language Model](https://mlsanity.com/paper/2305.10133/) (2023)
- [UniMoMo: Unified Generative Modeling of 3D Molecules for De Novo Binder Design](https://mlsanity.com/paper/2503.19300/) (2025)
- [Deep Learning Methods for Small Molecule Drug Discovery: A Survey](https://mlsanity.com/paper/2303.00313/) (2023)
- [Zero Shot Molecular Generation via Similarity Kernels](https://mlsanity.com/paper/2402.08708/) (2024)
- [Pharmacophore-Conditioned Diffusion Model for Ligand-Based De Novo Drug Design](https://mlsanity.com/paper/2505.10545/) (2025)

## Built on by (most cited first, 1 of 1)

- [Latent Retrieval Augmented Generation of Cross-Domain Protein Binders](https://mlsanity.com/paper/2510.10480/) (2025)

## Abstract (arXiv)

Structure-based drug design (SBDD) models are central to modern pharmaceutical research, enabling the rational exploration of protein-ligand interactions at atomic resolution. However, most existing approaches frame molecular generation as an isolated optimization or a one-to-one matching task, overlooking the shared binding patterns and intrinsic similarities among protein-ligand complexes. This fragmented perspective constrains their ability to capture the fundamental principles governing molecular recognition and binding specificity. Moreover, the limited availability of high-quality experimental data further hampers model generalization and real-world applicability. To address these challenges, we present READ, a retrieval-alignment molecular generation framework that conditions the generative process on small molecules targeting homologous proteins. Retrieved ligands are aligned with a diffusion model across multiple representational spaces and integrated as conditional guidance throughout successive stages of generation. Under a standardized docking-based evaluation protocol, READ achieves consistently strong performance against state-of-the-art SBDD methods. More importantly, it introduces a retrieval-alignment paradigm for structure-based molecular generation, offering a practical framework for early-stage computational hit generation while leaving prospective experimental validation as future work.