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

  • J Med Chem. 2026 May 28;69(10):11672-11686. doi: 10.1021/acs.jmedchem.6c00466.
Nan Zhang  1 ,  Li Teng  1 ,  Xiang Yu  1 ,  Zhiyong Wang  1 ,  Zhiping Zhang  1 ,  Zhao Dong  1 ,  Dongzhou Liu  1
Affiliations
  • 1. Huadong Global R&D Center, Hangzhou 310011, P. R. of China.
PMID: 42125916 DOI: 10.1021/acs.jmedchem.6c00466
Abstract

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 (T1/2 ∼ 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.

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