G蛋白偶联受体(GPCR)作为细胞感知外界信号的最大膜蛋白家族，已成为最重要的药物靶标，在生物学理论研究及创新药物研发中占有重要的地位。近年，针对GPCR信号转导提出的功能选择理论已经被科学界及制药业认同为发展新一代药物的重要理论依据。现有的药物发现方法亟待改良，以适应于寻找功能选择性配体。本课题拟以新发现的功能选择性配体及其结构学机理为切入点，建立一套以发现新的Gs信号通路选择性beta2肾上腺素受体激动剂为目标的药物研发策略和模式。结合改良现有的原代心肌细胞筛选技术，建立新的计算机模型，和研究化合物结构与活性、结构与特异性、结构与功能关系，等多学科交叉方法，更快速有效地发现具有生理活性的功能选择性配体。展望研究成果能确立一个路线图，加速功能选择性配体的发现向合理化药物设计的方向迈进，对开发新一代治疗心力衰竭的药物起积极作用。

G protein-coupled receptor (GPCR) is the most important class of drug targets and is a hotspot in biological research and drug development. Recently, the concept of functional selectivity, emerged to explain the multifaceted nature of GPCR signal transduction, has gradually gained acceptance by the academia and the pharmaceutical industry as a theoretical basis for new drug discovery. Presently, there is a dire need of new approaches to discover functionally selective or biased GPCR ligands. The aim of this project is to establish a strategic program to discover novel Gs-protein biased beta2-adrenoceptor agonists. Based on our recent breakthrough studies which have discovered a number of biased GPCR ligands and the structural basis for it, we intend to use a multidisciplinary approach comprising the development of new drug screening platforms, the development of new computational tools, and the combined use of medicinal chemistry principles in drug design and structure-activity/ structure-specificity/ structure-function relationship analysis to discover novel biased ligands. Our effort will develop a roadmap for the discovery of functionally selective GPCR ligands in a rational basis, with the ultimate aim to promote the discovery of novel medications for diseases such as heart failure.