mlsanityData to 14 Oct 2026

PepTune: De Novo Generation of Therapeutic Peptides with Multi-Objective-Guided Discrete Diffusion

arXiv 2412.17780 ↗First posted 23 Dec 2024q-bio.BM cs.AIcited by 37

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

Abstract (arXiv)

We present PepTune, a multi-objective discrete diffusion model for simultaneous generation and optimization of therapeutic peptide SMILES. Built on the Masked Discrete Language Model (MDLM) framework, PepTune ensures valid peptide structures with a novel bond-dependent masking schedule and invalid loss function. To guide the diffusion process, we introduce Monte Carlo Tree Guidance (MCTG), an inference-time multi-objective guidance algorithm that balances exploration and exploitation to iteratively refine Pareto-optimal sequences. MCTG integrates classifier-based rewards with search-tree expansion, overcoming gradient estimation challenges and data sparsity. Using PepTune, we generate diverse, chemically-modified peptides simultaneously optimized for multiple therapeutic properties, including target binding affinity, membrane permeability, solubility, hemolysis, and non-fouling for various disease-relevant targets. In total, our results demonstrate that MCTG for masked discrete diffusion is a powerful and modular approach for multi-objective sequence design in discrete state spaces.

Key facts. Cited by 37 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 18 of its 95 references that are in the map. First posted on arXiv 23 Dec 2024.

Builds on

18 of 95 references.

Closest ancestors · 7

Same direction, newest first

  1. 2024Steering Masked Discrete Diffusion Models via Discrete Denoising Posterior Prediction10 Oct
  2. 2024Discrete Flow Matching22 Jul
  3. 2024Fisher Flow Matching for Generative Modeling over Discrete Data23 May
  4. 2024Diffusion Language Models Are Versatile Protein Learners28 Feb
  5. 2024Dirichlet Flow Matching with Applications to DNA Sequence Design8 Feb
  6. 2023Protein Design with Guided Discrete Diffusion31 May
  7. 2022DiGress: Discrete Denoising diffusion for graph generation29 Sep

Other references · 11

  1. 2016XGBoost: A Scalable Tree Boosting Systemcited by 5,166
  2. 2021RoFormer: Enhanced Transformer with Rotary Position Embeddingcited by 4,703
  3. 2021Structured Denoising Diffusion Models in Discrete State-Spacescited by 1,719
  4. 2021Variational Diffusion Modelscited by 1,153
  5. 2024Simple and Effective Masked Diffusion Language Modelscited by 848
  6. 2023Discrete Diffusion Modeling by Estimating the Ratios of the Data Distributioncited by 745
  7. 2024Simplified and Generalized Masked Diffusion for Discrete Datacited by 626
  8. 2024Your Absorbing Discrete Diffusion Secretly Models the Conditional Distributions of Clean Datacited by 381
  9. 2018Molecular Sets (MOSES): A Benchmarking Platform for Molecular Generation Modelscited by 275
  10. 2024Masked Diffusion Models are Secretly Time-Agnostic Masked Models and Exploit Inaccurate Categorical Samplingcited by 208
  11. 2024Unlocking Guidance for Discrete State-Space Diffusion and Flow Modelscited by 129

Built on by

Cited by year (2026 to 14 Oct)

Citing papers per year: 2025: 15; 2026: 22.

37 papers.

Sort:

By area:

  1. 2025Discrete Diffusion in Large Language and Multimodal Models: A Surveycited by 61
  2. 2025MDNS: Masked Diffusion Neural Sampler via Stochastic Optimal Controlcited by 21
  3. 2025Enhancing Reasoning for Diffusion LLMs via Distribution Matching Policy Optimizationcited by 20
  4. 2025Multi-Objective-Guided Discrete Flow Matching for Controllable Biological Sequence Designcited by 15
  5. 2025TR2-D2: Tree Search Guided Trajectory-Aware Fine-Tuning for Discrete Diffusioncited by 14
  6. 2025Gumbel-Softmax Flow Matching with Straight-Through Guidance for Controllable Biological Sequence Generationcited by 11
  7. 2025Iterative Distillation for Reward-Guided Fine-Tuning of Diffusion Models in Biomolecular Designcited by 11
  8. 2026Discrete Feynman-Kac Correctorscited by 11
  9. 2025Steering Generative Models with Experimental Data for Protein Fitness Optimizationcited by 7
  10. 2025AReUReDi: Annealed Rectified Updates for Refining Discrete Flows with Multi-Objective Guidancecited by 5
  11. 2025Unified all-atom molecule generation with neural fieldscited by 3
  12. 2026Active Flow Expansion for Out-of-Distribution Discovery: from Theory to Moleculescited by 3
25 more
  1. 2025Designing Cyclic Peptides via Harmonic SDE with Atom-Bond Modelingcited by 2
  2. 2025Monte Carlo Tree Diffusion with Multiple Experts for Protein Designcited by 2
  3. 2026Diffusion Large Language Models for Black-Box Optimizationcited by 2
  4. 2026How to make the most of your masked language model for protein engineeringcited by 2
  5. 2026A2D2: Fine-Tuning Any-Length Discrete Diffusion for Adaptive Decodingcited by 2
  6. 2026Unlocking Lossless Speedups in LLMs via Discrete Diffusioncited by 2
  7. 2026TD3B: Transition-Directed Discrete Diffusion for Allosteric Binder Generationcited by 1
  8. 2026mRNAutilus: Multi-Objective-Guided Discrete Generation of mRNA with Optimized Therapeutic Propertiescited by 1
  9. 2026AlloGen: Conformation-Selective Binder Generation with Differential State Scoringcited by 1
  10. 2026Pepti-Agent: An AI Agent for Peptide Design and Optimizationcited by 1
  11. 2025Discovery of Sustainable Refrigerants through Physics-Informed RL Fine-Tuning of Sequence Modelscited by 0
  12. 2025Diffusion Models at the Drug Discovery Frontier: A Review on Generating Small Molecules versus Therapeutic Peptidescited by 0
  13. 2025PepEVOLVE: Position-Aware Dynamic Peptide Optimization via Group-Relative Advantagecited by 0
  14. 2026Minimal-Action Discrete Schr"odinger Bridge Matching for Peptide Sequence Designcited by 0
  15. 2026RosettaSearch: Multi-Objective Inference-Time Search for Protein Sequence Designcited by 0
  16. 2026Discrete Langevin-Inspired Posterior Samplingcited by 0
  17. 2026Flexible Flows for Biological Sequence Designcited by 0
  18. 2026PepALD: Macrocyclic Peptide Generation via Autoregressive Latent Diffusioncited by 0
  19. 2026Pepti-drift: Scalable Safe-Active Peptide Generation Without Inference-Time Guidancecited by 0
  20. 2026On the Design Space of Discrete Diffusion Online Adaptation for Molecular Optimizationcited by 0
  21. 2026FAR-DPO: Feasibility-Aware and Robust Direct Preference Optimization for Cyclic Peptide Designcited by 0
  22. 2026Benchmarking Peptide-Protein Affinity Prediction Across Peptide and Target Shiftscited by 0
  23. 2026pCoMole: Pareto-Constrained Molecule Editing with Discrete Flowscited by 0
  24. 2026DiMOS: Doob-Guided Inference-Time Multi-Objective Search for Scientific Designcited by 0
  25. 2026Bridging the Evidence-to-Execution Gap:A Reflective Agent for Multi-Objective Peptide Designcited by 0

Similar, not cited

Close in wording, no citation either way

  1. 2025PepThink-R1: LLM for Interpretable Cyclic Peptide Optimization with CoT SFT and Reinforcement Learning
  2. 2025Peptide2Mol: A Diffusion Model for Generating Small Molecules as Peptide Mimics for Targeted Protein Binding
  3. 2024PepINVENT: Generative peptide design beyond the natural amino acids
  4. 2026CAGenMol: Condition-Aware Diffusion Language Model for Goal-Directed Molecular Generation
  5. 2026Ligand-Conditioned Discrete Diffusion for Protein Sequence-Structure Co-Design
  6. 2026PepEDiff: Zero-Shot Peptide Binder Design via Protein Embedding Diffusion
  7. 2025Full-Atom Peptide Design via Riemannian-Euclidean Bayesian Flow Networks
  8. 2024Full-Atom Peptide Design based on Multi-modal Flow Matching