Structure-based development of bitopic GPCR ligands showing functional selectivity at β-adrenergic receptors

基于结构的双位 GPCR 配体开发显示 β 肾上腺素能受体的功能选择性

• 批准号: 528300906
• 负责人: Professor Dr. Peter Gmeiner
• 金额: --
• 依托单位: Institut für Pharmazie und Lebensmittelchemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/528300906?language=en
• 关键词: Structure; based; development; bitopic; GPCR

G protein-coupled receptors (GPCRs) are highly important pharmaceutical targets with multiple binding sites modulating their function. Apart from the orthosteric site, binding the native hormone/ neurotransmitter and an intracellular site recognizing a G protein or β-arrestin, allosteric binding sites located at the extracellular vestibule and the membrane-facing side of the receptor have been identified. Bitopic ligands are drugs or lead compounds comprising a pharmacophore for the orthosteric site and a second moiety specifically addressing an allosteric site. This project aims to design, synthesize and biologically investigate bitopic GPCR ligands based on an understanding of the structural and functional properties of each module and the impact of their ligation forming a bifunctional entity. The modules resulting from fragment-based virtual screening and chemical synthesis will be specifically functionalized and coupled, taking advantage of click chemistry. We will work on diffusible and covalently binding ligands. The computational compound design will be based on high-resolution structures (X-ray and cryo-EM structures) for a key player in cardiac physiology, the β-adrenergic receptor (βAR). Guided by docking, MD and FEP calculations, we will evolve bitopic lead compounds showing optimal complementarity and favorable interactions with two proximate receptor sites, the orthosteric binding pocket and the extracellular vestibule. Following a modular approach, we will probe synergistic or opposing properties between the two modules conferring the individual pharmacological profile of the bitopic ligands. Based on a structural understanding and cryo-EM structures of selected ligand-receptor complexes, the newly designed bitopic molecules will be optimized for their ability to activate the β2AR with Gi bias over Gs and β-arrestin.

G蛋白偶联受体（GPCR）是非常重要的药物靶标，具有多个调节其功能的结合位点。除了结合天然激素/神经递质的正构位点和识别G蛋白或β-抑制蛋白的细胞内位点之外，已经鉴定了位于细胞外前庭和受体的膜面向侧的变构结合位点。双位配体是包含用于正构位点的药效团和特异性寻址变构位点的第二部分的药物或先导化合物。该项目旨在设计，合成和生物学研究基于对每个模块的结构和功能特性以及它们连接形成双功能实体的影响的理解的双位GPCR配体。从基于片段的虚拟筛选和化学合成产生的模块将利用点击化学进行特异性功能化和偶联。我们将致力于扩散和共价结合配体。计算化合物设计将基于心脏生理学中的关键参与者β-肾上腺素能受体（βAR）的高分辨率结构（X射线和冷冻EM结构）。通过对接，MD和FEP计算的指导下，我们将发展的bitopic铅化合物显示最佳的互补性和良好的相互作用与两个邻近的受体位点，orthosteric结合口袋和细胞外前庭。按照模块化的方法，我们将探测两个模块之间的协同或相反的属性赋予个体的药理学特征的双位配体。基于对所选配体-受体复合物的结构理解和cryo-EM结构，新设计的双位分子将针对其激活β2AR的能力进行优化，其中Gi偏好超过Gs和β-抑制蛋白。