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

HDM1005 ( poterepatide ), a novel highly potent GLP-1/GIP dual agonist, was engineered via computational alanine scanning and rational acylation design. Nonacylated HDM1005 ( P001 ) showed stable receptor binding and higher affinity than nonacylated Tirzepatide in molecular dynamics simulations and MMGBSA calculation. Alanine scanning and steric clash analysis (radius of gyration) guided proper K24/28 acylation sites on P001 . Optimized linker and acyl chain design at K24 precisely tuned bioactivity and extended long-acting performance ( T 1/2 ∼ 20.3–23.1 h vs Tirzepatide ’s 9.21 h in mice). HDM1005 exerted 3-fold more potent HbAlc reduction in db/db mice and superior weight loss in DIO mice (39.97% vs 34.47%) versus Tirzepatide, 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, HDM1005 represents a potential best-in-class therapeutic agent for metabolic disorders.