# ActivityDiff: A diffusion model with Positive and Negative Activity Guidance for De Novo Drug Design

arXiv: https://arxiv.org/abs/2508.06364 · HTML: https://mlsanity.com/paper/2508.06364/

## Key facts

- Cited by 1 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 17 of its 56 references that are in the map.
- First posted on arXiv 8 Aug 2025.

## 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, 17 of 17)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)
- [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)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (2018)
- [Therapeutics Data Commons: Machine Learning Datasets and Tasks for Drug Discovery and Development](https://mlsanity.com/paper/2102.09548/) (2021)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)
- [Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design](https://mlsanity.com/paper/2210.05274/) (2022)
- [Objective-Reinforced Generative Adversarial Networks (ORGAN) for Sequence Generation Models](https://mlsanity.com/paper/1705.10843/) (2017)
- [DGL-LifeSci: An Open-Source Toolkit for Deep Learning on Graphs in Life Science](https://mlsanity.com/paper/2106.14232/) (2021)
- [Learning to design drug-like molecules in three-dimensional space using deep generative models](https://mlsanity.com/paper/2104.08474/) (2021)
- [Exploiting Pretrained Biochemical Language Models for Targeted Drug Design](https://mlsanity.com/paper/2209.00981/) (2022)
- [DTIAM: A unified framework for predicting drug-target interactions, binding affinities and activation/inhibition mechanisms](https://mlsanity.com/paper/2312.15252/) (2023)
- [MolMetaLM: a Physicochemical Knowledge-Guided Molecular Meta Language Model](https://mlsanity.com/paper/2411.15500/) (2024)

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

- [SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch](https://mlsanity.com/paper/2609.02963/) (2026)

## Abstract (arXiv)

Achieving precise control over a molecule's biological activity-encompassing targeted activation/inhibition, cooperative multi-target modulation, and off-target toxicity mitigation-remains a critical challenge in de novo drug design. However, existing generative methods primarily focus on producing molecules with a single desired activity, lacking integrated mechanisms for the simultaneous management of multiple intended and unintended molecular interactions. Here, we propose ActivityDiff, a generative approach based on the classifier-guidance technique of diffusion models. It leverages separately trained drug-target classifiers for both positive and negative guidance, enabling the model to enhance desired activities while minimizing harmful off-target effects. Experimental results show that ActivityDiff effectively handles essential drug design tasks, including single-/dual-target generation, fragment-constrained dual-target design, selective generation to enhance target specificity, and reduction of off-target effects. These results demonstrate the effectiveness of classifier-guided diffusion in balancing efficacy and safety in molecular design. Overall, our work introduces a novel paradigm for achieving integrated control over molecular activity, and provides ActivityDiff as a versatile and extensible framework.