期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 57, 期 10, 页码 2580-2585出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201708764
关键词
allostery; cannabinoid receptors; G-protein-coupled receptors; metadynamics
资金
- Stiftung Charite
- Berlin Institute of Health (BIH)
- Deutsche Forschungsgemeinschaft as part of the GRK1910 Medicinal Chemistry of Selective GPCR-Ligands
- Gauss Centre for Supercomputing [pr74su]
The cannabinoid CB1 receptor (CB1R) is an abundant metabotropic G-protein-coupled receptor that has been difficult to address therapeutically because of CNS side effects exerted by orthosteric drug candidates. Recent efforts have focused on developing allosteric modulators that target CB1R. Compounds from the recently discovered class of mixed agonistic and positive allosteric modulators (Ago-PAMs) based on 2-phenylindoles have shown promising functional and binding properties as CB1R ligands. Here, we identify binding modes of both the CP55,940 agonist and GAT228, a 2-phenylindole allosteric modulator, by using our metadynamics simulation protocol, and quantify their affinity and cooperativity by atomistic simulations. We demonstrate the involvement of multiple adjunct binding sites in the Ago-PAM characteristics of the 2-phenylindole modulators and explain their ability to compete with orthosteric agonists at higher concentrations. We validate these results experimentally by showing the contribution of multiple sites on the allosteric binding of ZCZ011, another homologous member of the class, together with the orthosteric agonist.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据