# Ensemble-Conditioned Molecular Design

arXiv: https://arxiv.org/abs/2609.15077 · HTML: https://mlsanity.com/paper/2609.15077/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 45 of its 88 references that are in the map.
- First posted on arXiv 14 Sep 2026.

## Builds on (most cited first, 30 of 45)

- [Diffusion Models Beat GANs on Image Synthesis](https://mlsanity.com/paper/2105.05233/) (2021)
- [Scalable Diffusion Models with Transformers](https://mlsanity.com/paper/2212.09748/) (2022)
- [Classifier-Free Diffusion Guidance](https://mlsanity.com/paper/2207.12598/) (2022)
- [Flow Matching for Generative Modeling](https://mlsanity.com/paper/2210.02747/) (2022)
- [Flow Straight and Fast: Learning to Generate and Transfer Data with Rectified Flow](https://mlsanity.com/paper/2209.03003/) (2022)
- [Building Normalizing Flows with Stochastic Interpolants](https://mlsanity.com/paper/2209.15571/) (2022)
- [Improving and generalizing flow-based generative models with minibatch optimal transport](https://mlsanity.com/paper/2302.00482/) (2023)
- [Compositional Visual Generation with Composable Diffusion Models](https://mlsanity.com/paper/2206.01714/) (2022)
- [Generative Flows on Discrete State-Spaces: Enabling Multimodal Flows with Applications to Protein Co-Design](https://mlsanity.com/paper/2402.04997/) (2024)
- [GEOM: Energy-annotated molecular conformations for property prediction and molecular generation](https://mlsanity.com/paper/2006.05531/) (2020)
- [Reduce, Reuse, Recycle: Compositional Generation with Energy-Based Diffusion Models and MCMC](https://mlsanity.com/paper/2302.11552/) (2023)
- [Understanding and Improving Layer Normalization](https://mlsanity.com/paper/1911.07013/) (2019)
- [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 flow matching](https://mlsanity.com/paper/2306.15030/) (2023)
- [Unlocking Guidance for Discrete State-Space Diffusion and Flow Models](https://mlsanity.com/paper/2406.01572/) (2024)
- [Feynman-Kac Correctors in Diffusion: Annealing, Guidance, and Product of Experts](https://mlsanity.com/paper/2503.02819/) (2025)
- [All-atom Diffusion Transformers: Unified generative modelling of molecules and materials](https://mlsanity.com/paper/2503.03965/) (2025)
- [Swallowing the Bitter Pill: Simplified Scalable Conformer Generation](https://mlsanity.com/paper/2311.17932/) (2023)
- [Navigating the Design Space of Equivariant Diffusion-Based Generative Models for De Novo 3D Molecule Generation](https://mlsanity.com/paper/2309.17296/) (2023)
- [SemlaFlow -- Efficient 3D Molecular Generation with Latent Attention and Equivariant Flow Matching](https://mlsanity.com/paper/2406.07266/) (2024)
- [The Importance of Being Scalable: Improving the Speed and Accuracy of Neural Network Interatomic Potentials Across Chemical Domains](https://mlsanity.com/paper/2410.24169/) (2024)
- [The Superposition of Diffusion Models Using the Ito Density Estimator](https://mlsanity.com/paper/2412.17762/) (2024)
- [FlowMol3: Flow Matching for 3D De Novo Small-Molecule Generation](https://mlsanity.com/paper/2508.12629/) (2025)
- [gRNAde: Geometric Deep Learning for 3D RNA inverse design](https://mlsanity.com/paper/2305.14749/) (2023)
- [Equivariant Shape-Conditioned Generation of 3D Molecules for Ligand-Based Drug Design](https://mlsanity.com/paper/2210.04893/) (2022)
- [PILOT: Equivariant diffusion for pocket conditioned de novo ligand generation with multi-objective guidance via importance sampling](https://mlsanity.com/paper/2405.14925/) (2024)
- [FLOWR: Flow Matching for Structure-Aware De Novo, Interaction- and Fragment-Based Ligand Generation](https://mlsanity.com/paper/2504.10564/) (2025)

## Abstract (arXiv)

Molecular design is typically approached as a problem of finding molecules which can adopt a single bioactive conformation. In reality, molecules occupy a distribution over conformations, and many of the properties which determine whether a candidate is viable depend on that distribution rather than on any single conformer. We reframe molecular design as an optimisation of both the modes and properties of molecules' conformational ensembles, where modes can be represented as shapes, pharmacophore profiles or protein pockets, and properties are aggregate scalars computed over the whole distribution. To realise this we introduce ensemble-conditioned guidance, a framework which conditions 3D molecular generative models on both axes simultaneously. Mode conditions are composed adaptively at inference by combining the vector fields produced under each condition. Conditions may be targeted or avoided, mixed across modalities and combined in arbitrary numbers, allowing a wide range of design tasks to be expressed with a single trained model. We introduce adaptive symmetry learning to allow conditions from different reference frames to be composed, and extend our generative framework to enable flexible-size generation. We evaluate on new benchmarks for multi-mode conditioning and ensemble property optimisation, and apply the framework to two practical drug discovery tasks, dual-target binder design and active-state-selective agonist design, where in both cases conditioning on the additional state improves the desired outcome over single-state conditioning.