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

ABSTRACT: 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, includ

SUBMITTER: Tang S 

PROVIDER: S-EPMC11703324 | biostudies-literature | 2025 Jun

REPOSITORIES: biostudies-literature