Diffusion Models for Macrocyclic Peptide Design Using Stability, Permeability, and Binding Constraints

Abstract

Macrocyclic peptides can address challenging therapeutic targets that are often poorly modulated by conventional small molecules or biologics, but their design is difficult because conformational preorganization, membrane permeability, and target binding are interdependent and sometimes competing requirements. Existing generative approaches for peptides often focus on sequence novelty or target affinity without fully accounting for the geometric constraints imposed by cyclization, highlighting t