Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of Cannabinoid CB1 Receptor Bound to a Negative Allosteric Modulator, ORG27569, and Analogs.
Membrane Lipids Are an Integral Part of Transmembrane Allosteric Sites in GPCRs: A Case Study of Cannabinoid CB1 Receptor Bound to a Negative Allosteric Modulator, ORG27569, and Analogs.
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DOI：
10.1021/acs.jmedchem.2c00946
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发表时间：
2022-09-22
影响因子：
7.3
通讯作者：
Natesan, Senthil
中科院分区：
文献类型：
--
作者：
Obi, Peter;Natesan, Senthil
越来越多的G蛋白偶联受体（GPCR）结构揭示了新的跨膜脂质暴露的变构位点。配体必须首先分配到周围的膜，并采取脂质路径到这些网站。值得注意的是，一个显着的一部分结合的配体似乎暴露于膜脂质。实验结构通常不考虑周围的脂质，它们对配体进入和结合的明显贡献经常被忽视和理解不足。使用经典的和增强的分子动力学模拟，我们表明，膜脂质是至关重要的ORG27569及其类似物在大麻素CB1受体的跨膜位点的访问和结合。所观察到的结合亲和力和协同性的差异来自主要与脂质相互作用的官能团。我们的研究结果表明，将膜脂作为跨膜位点的一个组成部分，用于准确表征，结合亲和力计算和药物发现中的铅优化的意义。
A growing number of G-protein-coupled receptor (GPCR) structures reveal novel transmembrane lipid-exposed allosteric sites. Ligands must first partition into the surrounding membrane and take lipid paths to these sites. Remarkably, a significant part of the bound ligands appears exposed to the membrane lipids. The experimental structures do not usually account for the surrounding lipids, and their apparent contribution to ligand access and binding is often overlooked and poorly understood. Using classical and enhanced molecular dynamics simulations, we show that membrane lipids are critical in the access and binding of ORG27569 and its analogs at the transmembrane site of cannabinoid CB1 receptor. The observed differences in the binding affinity and cooperativity arise from the functional groups that interact primarily with lipids. Our results demonstrate the significance of incorporating membrane lipids as an integral component of transmembrane sites for accurate characterization, binding-affinity calculations, and lead optimization in drug discovery.
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DOI：
10.1038/nrd2760
发表时间：
2009-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.5
作者：
Ferrari, Anna Maria;Degliesposti, Gianluca;Rastelli, Giulio
通讯作者：
Rastelli, Giulio
影响因子：
4.7
作者：
Ahn KH;Mahmoud MM;Samala S;Lu D;Kendall DA
通讯作者：
Kendall DA
DOI：
10.1038/nrd4308
发表时间：
2014-09
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.6
作者：
Greene, D'Artagnan;Qi, Ruxi;Luo, Ray
通讯作者：
Luo, Ray