Previously, drugs were developed focusing on target affinity and selectivity. However, it is becoming evident that the drug–target residence time, related to the off-rate, is an important parameter for successful drug development. The residence time influences both the on-rate and overall effectiveness of drugs. Furthermore, ligand binding is now appreciated to be a multistep process because metastable and/or intermediate binding sites in the extracellular region have been identified. In this review, we summarize experimental ligand-binding data for G-protein-coupled receptors (GPCRs), and their binding pathways, analyzed by molecular dynamics (MD). The kinetics of drug binding to GPCRs are complex and depend on several factors, including charge distribution on the receptor surface, ligand–receptor interactions in the binding channel and the binding site, or solvation.

以前，开发的药物着眼于靶标亲和力和选择性。但是，越来越明显的是，与脱靶率相关的药物-靶标停留时间是成功开发药物的重要参数。停留时间会影响药物的开通率和整体效力。此外，现在已经认识到配体结合是一个多步骤过程，因为已经确定了细胞外区域中的亚稳和/或中间结合位点。在这篇综述中，我们总结了通过分子动力学（MD）分析的G蛋白偶联受体（GPCR）的实验配体结合数据及其结合途径。药物与GPCR结合的动力学非常复杂，并且取决于多种因素，包括受体表面的电荷分布，