Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, 399 Royal Parade, Parkville 3052, Victoria, Australia.
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Department of Pharmacology, Monash University, 399 Royal Parade, Parkville 3052, Victoria, Australia.
Curr Opin Cell Biol. 2014 Apr;27:94-101. doi: 10.1016/j.ceb.2013.11.007. Epub 2013 Dec 22.
Traditionally, optimizing lead molecule interactions with the orthosteric site has been viewed as the best means for attaining selectivity at G protein-coupled receptors (GPCRs), but GPCRs possess spatially distinct allosteric sites that can also modulate receptor activity. Allosteric sites offer a greater potential for receptor subtype selectivity, the ability to fine-tune physiological responses, and the ability to engender signal pathway bias. The detection and quantification of allosteric drug candidates remain an ongoing challenge, but the development of novel analytical approaches for quantifying allostery is enriching structure-activity and structure-function studies of the phenomenon. Very recent breakthroughs in both structural and computational biology of GPCRs are also beginning to unravel the mechanistic basis of allosteric modulation at the molecular level.
传统上，优化先导分子与正构位点的相互作用被认为是在 G 蛋白偶联受体 (GPCR) 中获得选择性的最佳方法，但 GPCR 具有空间上不同的变构位点，也可以调节受体活性。变构位点为受体亚型选择性提供了更大的潜力，能够精细调节生理反应，并产生信号通路偏向。变构药物候选物的检测和定量仍然是一个持续的挑战，但用于定量变构的新型分析方法的发展正在丰富对该现象的结构-活性和结构-功能研究。GPCR 结构和计算生物学的最新突破也开始在分子水平上揭示变构调节的机制基础。
