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
Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
Department of Biochemistry and Molecular Biology, George S. Wise Faculty of Life Sciences, Tel-Aviv University , Ramat Aviv, Israel.
J Med Chem. 2017 Nov 22;60(22):9239-9250. doi: 10.1021/acs.jmedchem.7b01113. Epub 2017 Nov 13.
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 M 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.
毒蕈碱受体激动剂的特点是其叔胺或季胺以及它们与酯或相关中心的距离受到明显严格的限制。基于与iperoxo复合的毒蕈碱M受体的活性状态晶体结构，我们探索了缺乏先前已知配体高度保守功能的潜在激动剂。通过结构导向的药效团设计并随后进行对接，我们在19种对接并合成的化合物中发现了两种激动剂（化合物3和17），它们与受体契合良好，并预计会形成已知激动剂中保守的氢键。结构优化产生了化合物28，其效力比其母体3高4倍。基于这一新支架的发现，我们通过对接220万个片段寻找更广泛的化学类型，这揭示了另外三种与28或已知毒蕈碱无关的微摩尔级激动剂。即使像毒蕈碱这样定义严格且研究深入的口袋，也为基于结构的设计和新化学类型的发现提供了机会。
