# Diffusion Models at the Drug Discovery Frontier: A Review on Generating Small Molecules versus Therapeutic Peptides

arXiv: https://arxiv.org/abs/2511.00209 · HTML: https://mlsanity.com/paper/2511.00209/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Placed in Flow matching, time series and science, one of 14 directions in Diffusion models.
- Builds on 66 of its 247 references that are in the map.
- First posted on arXiv 31 Oct 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, 30 of 66)

- [Denoising Diffusion Probabilistic Models](https://mlsanity.com/paper/2006.11239/) (2020)
- [High-Resolution Image Synthesis with Latent Diffusion Models](https://mlsanity.com/paper/2112.10752/) (2021)
- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [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)
- [Generative Modeling by Estimating Gradients of the Data Distribution](https://mlsanity.com/paper/1907.05600/) (2019)
- [Density estimation using Real NVP](https://mlsanity.com/paper/1605.08803/) (2016)
- [Imagen Video: High Definition Video Generation with Diffusion Models](https://mlsanity.com/paper/2210.02303/) (2022)
- [Structured Denoising Diffusion Models in Discrete State-Spaces](https://mlsanity.com/paper/2107.03006/) (2021)
- [DiffWave: A Versatile Diffusion Model for Audio Synthesis](https://mlsanity.com/paper/2009.09761/) (2020)
- [Diffusion-LM Improves Controllable Text Generation](https://mlsanity.com/paper/2205.14217/) (2022)
- [E(n) Equivariant Graph Neural Networks](https://mlsanity.com/paper/2102.09844/) (2021)
- [Masked Autoregressive Flow for Density Estimation](https://mlsanity.com/paper/1705.07057/) (2017)
- [Equivariant Diffusion for Molecule Generation in 3D](https://mlsanity.com/paper/2203.17003/) (2022)
- [Junction Tree Variational Autoencoder for Molecular Graph Generation](https://mlsanity.com/paper/1802.04364/) (2018)
- [Improving Variational Inference with Inverse Autoregressive Flow](https://mlsanity.com/paper/1606.04934/) (2016)
- [DiGress: Discrete Denoising diffusion for graph generation](https://mlsanity.com/paper/2209.14734/) (2022)
- [GeoDiff: a Geometric Diffusion Model for Molecular Conformation Generation](https://mlsanity.com/paper/2203.02923/) (2022)
- [MolGAN: An implicit generative model for small molecular graphs](https://mlsanity.com/paper/1805.11973/) (2018)
- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [GraphAF: a Flow-based Autoregressive Model for Molecular Graph Generation](https://mlsanity.com/paper/2001.09382/) (2020)
- [GuacaMol: Benchmarking Models for De Novo Molecular Design](https://mlsanity.com/paper/1811.09621/) (2018)
- [Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Models](https://mlsanity.com/paper/1811.12823/) (2018)
- [Deep Generative Modelling: A Comparative Review of VAEs, GANs, Normalizing Flows, Energy-Based and Autoregressive Models](https://mlsanity.com/paper/2103.04922/) (2021)
- [Structure-based Drug Design with Equivariant Diffusion Models](https://mlsanity.com/paper/2210.13695/) (2022)
- [Speech Enhancement and Dereverberation with Diffusion-based Generative Models](https://mlsanity.com/paper/2208.05830/) (2022)
- [MoFlow: An Invertible Flow Model for Generating Molecular Graphs](https://mlsanity.com/paper/2006.10137/) (2020)
- [Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pockets](https://mlsanity.com/paper/2205.07249/) (2022)

## Abstract (arXiv)

Diffusion models have emerged as a leading framework in generative modeling, poised to transform the traditionally slow and costly process of drug discovery. This review provides a systematic comparison of their application in designing two principal therapeutic modalities: small molecules and therapeutic peptides. We dissect how the unified framework of iterative denoising is adapted to the distinct molecular representations, chemical spaces, and design objectives of each modality. For small molecules, these models excel at structure-based design, generating novel, pocket-fitting ligands with desired physicochemical properties, yet face the critical hurdle of ensuring chemical synthesizability. Conversely, for therapeutic peptides, the focus shifts to generating functional sequences and designing de novo structures, where the primary challenges are achieving biological stability against proteolysis, ensuring proper folding, and minimizing immunogenicity. Despite these distinct challenges, both domains face shared hurdles: the scarcity of high-quality experimental data, the reliance on inaccurate scoring functions for validation, and the crucial need for experimental validation. We conclude that the full potential of diffusion models will be unlocked by bridging these modality-specific gaps and integrating them into automated, closed-loop Design-Build-Test-Learn (DBTL) platforms, thereby shifting the paradigm from mere chemical exploration to the on-demand engineering of novel~therapeutics.