# General Binding Affinity Guidance for Diffusion Models in Structure-Based Drug Design

arXiv: https://arxiv.org/abs/2406.16821 · HTML: https://mlsanity.com/paper/2406.16821/

## Key facts

- Cited by 5 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 26 of its 47 references that are in the map.
- First posted on arXiv 24 Jun 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, 26 of 26)

- [Adam: A Method for Stochastic Optimization](https://mlsanity.com/paper/1412.6980/) (2014)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Score-Based Generative Modeling through Stochastic Differential Equations](https://mlsanity.com/paper/2011.13456/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [GLIDE: Towards Photorealistic Image Generation and Editing with Text-Guided Diffusion Models](https://mlsanity.com/paper/2112.10741/) (2021)
- [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)
- [Universal Guidance for Diffusion Models](https://mlsanity.com/paper/2302.07121/) (2023)
- [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)
- [Independent SE(3)-Equivariant Models for End-to-End Rigid Protein Docking](https://mlsanity.com/paper/2111.07786/) (2021)
- [Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Models](https://mlsanity.com/paper/2110.15200/) (2021)
- [Equivariant Energy-Guided SDE for Inverse Molecular Design](https://mlsanity.com/paper/2209.15408/) (2022)
- [The Synthesizability of Molecules Proposed by Generative Models](https://mlsanity.com/paper/2002.07007/) (2020)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [DecompOpt: Controllable and Decomposed Diffusion Models for Structure-based Molecular Optimization](https://mlsanity.com/paper/2403.13829/) (2024)
- [Binding-Adaptive Diffusion Models for Structure-Based Drug Design](https://mlsanity.com/paper/2402.18583/) (2024)
- [Rethinking Specificity in SBDD: Leveraging Delta Score and Energy-Guided Diffusion](https://mlsanity.com/paper/2403.12987/) (2024)
- [CoarsenConf: Equivariant Coarsening with Aggregated Attention for Molecular Conformer Generation](https://mlsanity.com/paper/2306.14852/) (2023)

## Built on by (most cited first, 5 of 5)

- [ParetoFlow: Guided Flows in Multi-Objective Optimization](https://mlsanity.com/paper/2412.03718/) (2024)
- [Are we really tilting? The mechanics of reward guidance in flow and diffusion models](https://mlsanity.com/paper/2606.02884/) (2026)
- [KinetiDiff: Docking-Guided Diffusion for De Novo ACVR1 Inhibitor Design in Fibrodysplasia Ossificans Progressiva](https://mlsanity.com/paper/2604.20886/) (2026)
- [On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimization](https://mlsanity.com/paper/2607.02834/) (2026)
- [PocketVE: Stable and Property-Guided Structure-Based Drug Design with Variance-Exploding Diffusion](https://mlsanity.com/paper/2609.08101/) (2026)

## Abstract (arXiv)

Structure-based drug design (SBDD) aims to generate ligands that bind strongly and specifically to target protein pockets. Recent diffusion models have advanced SBDD by capturing the distributions of atomic positions and types, yet they often underemphasize binding affinity control during generation. To address this limitation, we introduce textbftextnormalBADGER, a general binding-affinity guidance framework for diffusion models in SBDD. textnormalBADGER incorporates binding affinity awareness through two complementary strategies: (1) textitclassifier guidance, which applies gradient-based affinity signals during sampling in a plug-and-play fashion, and (2) textitclassifier-free guidance, which integrates affinity conditioning directly into diffusion model training. Together, these approaches enable controllable ligand generation guided by binding affinity. textnormalBADGER  can be added to any diffusion model and achieves up to a 60% improvement in ligand--protein binding affinity of sampled molecules over prior methods. Furthermore, we extend the framework to multi-constraint diffusion guidance, jointly optimizing for binding affinity, drug-likeness (QED), and synthetic accessibility (SA) to design realistic and synthesizable drug candidates.