Structure-Based Design and Discovery of New M2 Receptor Agonists
| Autor: | Fish, Inbar, Stößel, Anne, Eitel, Katrin, Valant, Celine, Albold, Sabine, Huebner, Harald, Möller, Dorothee, Clark, Mary J, Sunahara, Roger K, Christopoulos, Arthur, Shoichet, Brian K, Gmeiner, Peter |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Medicinal & Biomolecular Chemistry
CHO Cells Muscarinic Agonists Tritium Nicotinic Ligands Medicinal and Biomolecular Chemistry Cricetulus Receptors Animals Humans Benzofurans Arrestin Organic Chemistry Isoxazoles Pharmacology and Pharmaceutical Sciences N-Methylscopolamine Acetylcholine Brain Disorders Quaternary Ammonium Compounds Molecular Docking Simulation Muscarinic M3 HEK293 Cells Muscarinic M2 Muscarinic M1 Drug Design Carbachol Receptor |
| Zdroj: | Journal of medicinal chemistry, vol 60, iss 22 |
| Popis: | Muscarinic receptor agonists are characterized by apparently strict restraints on their tertiary or quaternary amine and their distance to an ester or related center. On the basis of the active state crystal structure of the muscarinic M2 receptor in complex with iperoxo, we explored potential agonists that lacked the highly conserved functionalities of previously known ligands. Using structure-guided pharmacophore design followed by docking, we found two agonists (compounds 3 and 17), out of 19 docked and synthesized compounds, that fit the receptor well and were predicted to form a hydrogen-bond conserved among known agonists. Structural optimization led to compound 28, which was 4-fold more potent than its parent 3. Fortified by the discovery of this new scaffold, we sought a broader range of chemotypes by docking 2.2 million fragments, which revealed another three micromolar agonists unrelated either to 28 or known muscarinics. Even pockets as tightly defined and as deeply studied as that of the muscarinic reveal opportunities for the structure-based design and the discovery of new chemotypes. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|