Abstract：
G protein-coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational drug design for GPCRs has mainly focused on static structures obtained through X-ray crystallography, cryogenic electron microscopy (cryo-EM) or in silico modelling as a starting point for virtual screening campaigns. However, GPCRs are highly flexible entities with the ability to adopt different conformational states that elicit different physiological responses. Including this knowledge in the drug discovery pipeline can help to tailor novel conformation-specific drugs with an improved therapeutic profile. In this review, we outline our current knowledge about GPCR dynamics that is relevant for receptor activation, signalling bias and allosteric modulation. Ultimately, we highlight new technological implementations such as time-resolved X-ray crystallography and cryo-EM as well as computational algorithms that can contribute to a more comprehensive understanding of receptor dynamics and its relevance for GPCR functionality.
摘要：
G蛋白偶联受体(GPCRs)是主要的药物靶标之一。近年来,GPCRs的计算药物设计主要集中在通过X射线晶体学获得的静态结构，低温电子显微镜（cryo-EM）或计算机模拟作为虚拟筛查活动的起点。然而,GPCR是高度灵活的实体,具有采用引起不同生理反应的不同构象状态的能力。在药物发现管道中包括这些知识可以帮助定制具有改善的治疗概况的新型构象特异性药物。在这次审查中,我们概述了我们目前关于受体激活相关的GPCR动力学的知识，信号偏置和变构调制。最终,我们重点介绍了新的技术实现，例如时间分辨X射线晶体学和低温EM以及计算算法，这些算法可以有助于更全面地了解受体动力学及其与GPCR功能的相关性。
