Orforglipron: difference between revisions
Diff·revision 2 → 3·10:49, 3 Dec 2024
Difference between revision 2 and revision 3 of Orforglipron. 5 lines changed; the page grew by 781 bytes.
| Revision 2 — 10:24, 22 Nov 2024 SemaglutideSasha (talk) British spelling per PP:MOS 1,574 bytes ±0 | Revision 3 — 10:49, 3 Dec 2024 RetatrutideRuben (talk) reorder the analogues chronologically rather than alphabetically 2,355 bytes +781 | ||
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| 11 | Small-molecule agonism at a class B G-protein-coupled receptor was long considered difficult, because the natural ligand engages a large surface across two receptor domains.{{r|graaf2016}} Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.{{r|kawai2020}} | 11 | Small-molecule agonism at a class B G-protein-coupled receptor was long considered difficult, because the natural ligand engages a large surface across two receptor domains.{{r|graaf2016}} Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.{{r|kawai2020}} |
| 12 | 12 | ||
| + | 13 | == Molecular basis == | |
| + | 14 | The receptor's orthosteric peptide site is a poor target for a small molecule: the natural ligand contacts both the extracellular domain and the transmembrane bundle across a large interface, and a molecule of a few hundred daltons cannot reproduce that. Orforglipron instead occupies a pocket accessible from the extracellular face of the bundle and acts as an agonist by stabilising the same active receptor conformation by a different route.{{r|kawai2020}} | |
| + | 15 | ||
| + | 16 | A consequence is species selectivity. The pocket differs between human and rodent receptors sufficiently that activity does not translate, and preclinical work required humanised receptor models — a practical complication of small-molecule work at this target that peptide agonists do not face. | |
| + | 17 | ||
| 13 | == References == | 18 | == References == |
| 14 | {{reflist}} | 19 | {{reflist}} |