Variant-specific pharmacophoric shifts in glucagon-like peptide-1 receptor-orforglipron complexes revealed by Boltz-2 co-folding and membrane molecular dynamics.

Abstract excerpt

BACKGROUND: Orforglipron (ORF), the first orally bioavailable non-peptide glucagon-like peptide-1 receptor (GLP-1R) agonist to complete Phase 3 clinical trials, binds a distinct extracellular vestibule pocket not engaged by peptide GLP-1RAs. How commonly GLP-1R single-nucleotide polymorphisms alter this unique binding mode at the molecular level remains uncharacterized. METHODS: We employed an integrative...

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• Glucagon-Like Peptide-1 Receptor
• Hydrogen Bonding
• Ligands
• Lipid Bilayers
• Molecular Dynamics Simulation
• Oxadiazoles