Changes in drug binding sites of glucagon-like peptide-1 receptor complexes with orforglipron studied using advanced folding and membrane simulations

Orforglipron (ORF) is the first orally bioavailable non-peptide GLP-1 receptor agonist to complete Phase 3 clinical trials.

• ORF binds a unique pocket on the GLP-1 receptor that peptide GLP-1 receptor agonists do not engage.
• The impact of single-nucleotide polymorphisms in the GLP-1 receptor on ORF binding has not been characterized.
• This study highlights a potential difference in binding mechanisms between non-peptide and peptide GLP-1 receptor agonists.

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