Discovery of a High-Potency Balanced GLP-1/GIP Dual Agonist by Molecular Dynamics Evolution.

(), a novel highly potent GLP-1/GIP dual agonist, was engineered via computational alanine scanning and rational acylation design. Nonacylated () showed stable receptor binding and higher affinity than nonacylated in molecular dynamics simulations and MMGBSA calculation. Alanine scanning and steric clash analysis (radius of gyration) guided proper K24/28 acylation sites on . Optimized linker and acyl chain design at K24 precisely tuned bioactivity and extended long-acting performance ( ∼ 20.3-23.1 h vs 's 9.21 h in mice). exerted 3-fold more potent HbAlc reduction in mice and superior weight loss in DIO mice (39.97% vs 34.47%) versus , yielding enhanced metabolic benefits, plus preferential fat loss with lean mass preservation in obese mice. It exhibited a favorable safety profile with a NOAEL of 5 mg/kg. With enhanced receptor binding, extended pharmacodynamic activity, and superior efficacy, represents a potential best-in-class therapeutic agent for metabolic disorders.