mlsanityData to 7 Oct 2026

Multi-domain Distribution Learning for De Novo Drug Design

arXiv 2508.17815 ↗First posted 25 Aug 2025cs.LG q-bio.BMcited by 15

On the map: Diffusion models → Flow matching, time series and science

Abstract (arXiv)

We introduce DrugFlow, a generative model for structure-based drug design that integrates continuous flow matching with discrete Markov bridges, demonstrating state-of-the-art performance in learning chemical, geometric, and physical aspects of three-dimensional protein-ligand data. We endow DrugFlow with an uncertainty estimate that is able to detect out-of-distribution samples. To further enhance the sampling process towards distribution regions with desirable metric values, we propose a joint preference alignment scheme applicable to both flow matching and Markov bridge frameworks. Furthermore, we extend our model to also explore the conformational landscape of the protein by jointly sampling side chain angles and molecules.

Key facts. Cited by 15 papers in the map (data through 7 Oct 2026). Placed in Flow matching, time series and science, one of 14 directions in Diffusion models. Builds on 45 of its 77 references that are in the map. First posted on arXiv 25 Aug 2025.

Builds on

45 of 77 references.

Closest ancestors · 15

Same direction, newest first

  1. 2024Decomposed Direct Preference Optimization for Structure-Based Drug Design19 Jul
  2. 2024Aligning Target-Aware Molecule Diffusion Models with Exact Energy Optimization1 Jul
  3. 2024Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation30 Apr
  4. 2024DecompDiff: Diffusion Models with Decomposed Priors for Structure-Based Drug Design26 Feb
  5. 2023Equivariant Flow Matching with Hybrid Probability Transport12 Dec
  6. 2023Geometric Latent Diffusion Models for 3D Molecule Generation2 May
  7. 2023MiDi: Mixed Graph and 3D Denoising Diffusion for Molecule Generation17 Feb
  8. 2023SE(3) diffusion model with application to protein backbone generation5 Feb
  9. 2023Improving and generalizing flow-based generative models with minibatch optimal transport1 Feb
  10. 2022Structure-based Drug Design with Equivariant Diffusion Models24 Oct
  11. 2022Equivariant 3D-Conditional Diffusion Models for Molecular Linker Design11 Oct
  12. 2022Flow Matching for Generative Modeling6 Oct
3 more
  1. 2022DiGress: Discrete Denoising diffusion for graph generation29 Sep
  2. 2022Equivariant Diffusion for Molecule Generation in 3D31 Mar
  3. 2022Score-based Generative Modeling of Graphs via the System of Stochastic Differential Equations5 Feb

Other references · 30

  1. 2023Direct Preference Optimization: Your Language Model is Secretly a Reward Modelcited by 7,916
  2. 2016Simple and Scalable Predictive Uncertainty Estimation using Deep Ensemblescited by 3,888
  3. 2021Structured Denoising Diffusion Models in Discrete State-Spacescited by 1,665
  4. 2022Building Normalizing Flows with Stochastic Interpolantscited by 964
  5. 2023Diffusion Model Alignment Using Direct Preference Optimizationcited by 767
  6. 2016Automatic chemical design using a data-driven continuous representation of moleculescited by 762
  7. 2022Analog Bits: Generating Discrete Data using Diffusion Models with Self-Conditioningcited by 362
  8. 2020Learning from Protein Structure with Geometric Vector Perceptronscited by 308
  9. 2022DiffDock: Diffusion Steps, Twists, and Turns for Molecular Dockingcited by 307
  10. 2018Optimization of Molecules via Deep Reinforcement Learningcited by 199
  11. 2018Fr'echet ChemNet Distance: A metric for generative models for molecules in drug discoverycited by 191
  12. 2022Pocket2Mol: Efficient Molecular Sampling Based on 3D Protein Pocketscited by 182
18 more
  1. 20233D Equivariant Diffusion for Target-Aware Molecule Generation and Affinity Predictioncited by 176
  2. 2019Symmetry-adapted generation of 3d point sets for the targeted discovery of moleculescited by 171
  3. 2021E(n) Equivariant Normalizing Flowscited by 165
  4. 2017Deep Reinforcement Learning for De-Novo Drug Designcited by 161
  5. 2022A 3D Generative Model for Structure-Based Drug Designcited by 148
  6. 2022Generating 3D Molecules for Target Protein Bindingcited by 104
  7. 2021Generating 3D Molecules Conditional on Receptor Binding Sites with Deep Generative Modelscited by 72
  8. 2019Mol-CycleGAN - a generative model for molecular optimizationcited by 66
  9. 2022DiffBP: Generative Diffusion of 3D Molecules for Target Protein Bindingcited by 58
  10. 2020Learning To Navigate The Synthetically Accessible Chemical Space Using Reinforcement Learningcited by 57
  11. 2021Equivariant Graph Neural Networks for 3D Macromolecular Structurecited by 53
  12. 2023RetroBridge: Modeling Retrosynthesis with Markov Bridgescited by 35
  13. 2023Trans-Dimensional Generative Modeling via Jump Diffusion Modelscited by 33
  14. 2024Antigen-Specific Antibody Design via Direct Energy-based Preference Optimizationcited by 30
  15. 2023Harmonic Self-Conditioned Flow Matching for Multi-Ligand Docking and Binding Site Designcited by 29
  16. 2024PPFlow: Target-aware Peptide Design with Torsional Flow Matchingcited by 26
  17. 2024PILOT: Equivariant diffusion for pocket conditioned de novo ligand generation with multi-objective guidance via importance samplingcited by 19
  18. 2023Preference Optimization for Molecular Language Modelscited by 6

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Cited by year (2026 to 7 Oct)

Citing papers per year: 2025: 7; 2026: 8.

15 papers.

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  1. 2025Branching Flows: Discrete, Continuous, and Manifold Flow Matching with Splits and Deletionscited by 4
  2. 2026Mozi: Governed Autonomy for Drug Discovery LLM Agentscited by 4
  3. 2025MiAD: Mirage Atom Diffusion for De Novo Crystal Generationcited by 3
  4. 2025FLOWR.root: A flow matching based foundation model for joint multi-purpose structure-aware 3D ligand generation and affinity predictioncited by 2
  5. 2025NEAT: Neighborhood-Guided, Efficient, Autoregressive Set Transformer for 3D Molecular Generationcited by 2
  6. 2025Predictive Feature Caching for Training-free Acceleration of Molecular Geometry Generationcited by 1
  7. 2025Flow-Based Fragment Identification via Binding Site-Specific Latent Representationscited by 0
  8. 2025OMTRA: A Multi-Task Generative Model for Structure-Based Drug Designcited by 0
  9. 2026MacroGuide: Topological Guidance for Macrocycle Generationcited by 0
  10. 2026Demystifying Multimodal Biomolecular Co-design With Intrinsic Geodesic Couplingcited by 0
  11. 2026SynLaD: Latent Diffusion for Generating Synthesizable Molecules Conditioned on 3D Pharmacophore Profilescited by 0
  12. 2026HEDGEHOG: Hierarchical Evaluation of Drug Generators Through Rigorous Filtrationcited by 0
3 more
  1. 2026CORAL: Learning Amyloid Fibril Ligand Docking with Cooperative Binding Rewardscited by 0
  2. 2026Language-Informed Flow Matching for Trend-Guided Structure-Based 3D Molecular Generationcited by 0
  3. 2026Ensemble-Conditioned Molecular Designcited by 0

Similar, not cited

Close in wording, no citation either way

  1. 2024Exploring Discrete Flow Matching for 3D De Novo Molecule Generation
  2. 2025Prior-Guided Flow Matching for Target-Aware Molecule Design with Learnable Atom Number
  3. 2024Rectified Flow For Structure Based Drug Design
  4. 2025FlowMol3: Flow Matching for 3D De Novo Small-Molecule Generation
  5. 2025FlexiFlow: decomposable flow matching for generation of flexible molecular ensemble
  6. 2024FlowDock: Geometric Flow Matching for Generative Protein-Ligand Docking and Affinity Prediction
  7. 2024Full-Atom Peptide Design based on Multi-modal Flow Matching
  8. 2025Compositional Flows for 3D Molecule and Synthesis Pathway Co-design