# Context-Guided Diffusion for Out-of-Distribution Molecular and Protein Design

arXiv: https://arxiv.org/abs/2407.11942 · HTML: https://mlsanity.com/paper/2407.11942/

## Key facts

- Cited by 11 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 58 of its 105 references that are in the map.
- First posted on arXiv 16 Jul 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 58)

- [Language Models are Few-Shot Learners](https://mlsanity.com/paper/2005.14165/) (2020)
- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [PyTorch: An Imperative Style, High-Performance Deep Learning Library](https://mlsanity.com/paper/1912.01703/) (2019)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Semi-Supervised Classification with Graph Convolutional Networks](https://mlsanity.com/paper/1609.02907/) (2016)
- [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)
- [Explaining and Harnessing Adversarial Examples](https://mlsanity.com/paper/1412.6572/) (2014)
- [Deep Unsupervised Learning using Nonequilibrium Thermodynamics](https://mlsanity.com/paper/1503.03585/) (2015)
- [Hierarchical Text-Conditional Image Generation with CLIP Latents](https://mlsanity.com/paper/2204.06125/) (2022)
- [Photorealistic Text-to-Image Diffusion Models with Deep Language Understanding](https://mlsanity.com/paper/2205.11487/) (2022)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Adding Conditional Control to Text-to-Image Diffusion Models](https://mlsanity.com/paper/2302.05543/) (2023)
- [Intriguing properties of neural networks](https://mlsanity.com/paper/1312.6199/) (2013)
- [On the Opportunities and Risks of Foundation Models](https://mlsanity.com/paper/2108.07258/) (2021)
- [Simple and Scalable Predictive Uncertainty Estimation using Deep Ensembles](https://mlsanity.com/paper/1612.01474/) (2016)
- [Improved Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2102.09672/) (2021)
- [GLIDE: Towards Photorealistic Image Generation and Editing with Text-Guided Diffusion Models](https://mlsanity.com/paper/2112.10741/) (2021)
- [Elucidating the Design Space of Diffusion-Based Generative Models](https://mlsanity.com/paper/2206.00364/) (2022)
- [Domain-Adversarial Training of Neural Networks](https://mlsanity.com/paper/1505.07818/) (2015)
- [UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction](https://mlsanity.com/paper/1802.03426/) (2018)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [MixMatch: A Holistic Approach to Semi-Supervised Learning](https://mlsanity.com/paper/1905.02249/) (2019)
- [WILDS: A Benchmark of in-the-Wild Distribution Shifts](https://mlsanity.com/paper/2012.07421/) (2020)
- [Can You Trust Your Model's Uncertainty? Evaluating Predictive Uncertainty Under Dataset Shift](https://mlsanity.com/paper/1906.02530/) (2019)
- [Deep CORAL: Correlation Alignment for Deep Domain Adaptation](https://mlsanity.com/paper/1607.01719/) (2016)
- [Fast and Accurate Deep Network Learning by Exponential Linear Units (ELUs)](https://mlsanity.com/paper/1511.07289/) (2015)
- [Temporal Ensembling for Semi-Supervised Learning](https://mlsanity.com/paper/1610.02242/) (2016)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Automatic chemical design using a data-driven continuous representation of molecules](https://mlsanity.com/paper/1610.02415/) (2016)

## Built on by (most cited first, 11 of 11)

- [Steering Generative Models with Experimental Data for Protein Fitness Optimization](https://mlsanity.com/paper/2505.15093/) (2025)
- [Verifier-Constrained Flow Expansion for Discovery Beyond the Data](https://mlsanity.com/paper/2602.15984/) (2026)
- [Chemistry-Inspired Diffusion with Non-Differentiable Guidance](https://mlsanity.com/paper/2410.06502/) (2024)
- [G2D2: Gradient-Guided Discrete Diffusion for Inverse Problem Solving](https://mlsanity.com/paper/2410.14710/) (2024)
- [Diffusion Twigs with Loop Guidance for Conditional Graph Generation](https://mlsanity.com/paper/2410.24012/) (2024)
- [Amortized Active Generation of Pareto Sets](https://mlsanity.com/paper/2510.21052/) (2025)
- [Sampling Out-of-Distribution Chemical Spaces via Bayesian Flow](https://mlsanity.com/paper/2412.11439/) (2024)
- [ReconMOST: Multi-Layer Sea Temperature Reconstruction with Observations-Guided Diffusion](https://mlsanity.com/paper/2506.10391/) (2025)
- [Demystify Protein Generation with Hierarchical Conditional Diffusion Models](https://mlsanity.com/paper/2507.18603/) (2025)
- [Diffusion Models at the Drug Discovery Frontier: A Review on Generating Small Molecules versus Therapeutic Peptides](https://mlsanity.com/paper/2511.00209/) (2025)
- [From Snapshots to Symphonies: The Evolution of Protein Prediction from Static Structures to Generative Dynamics and Multimodal Interactions](https://mlsanity.com/paper/2603.18505/) (2026)

## Abstract (arXiv)

Generative models have the potential to accelerate key steps in the discovery of novel molecular therapeutics and materials. Diffusion models have recently emerged as a powerful approach, excelling at unconditional sample generation and, with data-driven guidance, conditional generation within their training domain. Reliably sampling from high-value regions beyond the training data, however, remains an open challenge -- with current methods predominantly focusing on modifying the diffusion process itself. In this paper, we develop context-guided diffusion (CGD), a simple plug-and-play method that leverages unlabeled data and smoothness constraints to improve the out-of-distribution generalization of guided diffusion models. We demonstrate that this approach leads to substantial performance gains across various settings, including continuous, discrete, and graph-structured diffusion processes with applications across drug discovery, materials science, and protein design.