Applied Biotechnology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States.
Biochem Pharmacol. 2011 Mar 15;81(6):691-702. doi: 10.1016/j.bcp.2010.12.012. Epub 2010 Dec 22.
Once considered a pharmacological curiosity, allosteric modulation of seven transmembrane domain G-protein-coupled receptors (GPCRs) has emerged as a potentially powerful means to affect receptor function for therapeutic purposes. Allosteric modulators, which interact with binding sites topologically distinct from the orthosteric ligand binding sites, can potentially provide improved selectivity and safety, along with maintenance of spatial and temporal aspects of GPCR signaling. Accordingly, drug discovery efforts for GPCRs have increasingly focused on the identification of allosteric modulators. This review is devoted to an examination of the strategies, challenges, and opportunities for high-throughput screening for allosteric modulators of GPCRs, with particular focus on the identification of positive allosteric modulators.
曾经被认为是药理学上的新奇事物，七跨膜域 G 蛋白偶联受体 (GPCR) 的变构调节已成为一种潜在的有效方法，可以用于治疗目的来影响受体功能。变构调节剂与位于变构配体结合位点拓扑上不同的结合位点相互作用，有可能提供更好的选择性和安全性，同时保持 GPCR 信号的空间和时间方面。因此，GPCR 的药物发现工作越来越集中于变构调节剂的鉴定上。本文综述了高通量筛选 GPCR 变构调节剂的策略、挑战和机遇，特别关注阳性变构调节剂的鉴定。
