Elucidating the molecular mechanism of biased signaling at the serotonin 2A receptor for the design of new-generation neuropsychiatric medications

阐明血清素 2A 受体偏向信号传导的分子机制，用于设计新一代神经精神药物

• 批准号: 471315262
• 负责人: Dr. Marc André Dämgen
• 金额: --
• 依托单位: Computer Science Department
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/471315262?language=en
• 关键词: Elucidating; molecular; mechanism; biased; signaling

G-protein-coupled receptors (GPCRs) are the largest class of human membrane proteins and control virtually all aspects of our physiology. More than a third of all drugs rely on interactions with GPCRs for the treatment of a wide range of diseases, including neuropsychiatric disorders, cancer, and Alzheimer’s. Upon binding of extracellular signaling molecules, GPCRs change their shape and couple to intracellular transducer proteins, such as G-proteins and arrestins, which activate different intracellular signaling cascades. The discovery that certain molecules, that bind to the same binding site in a GPCR, can selectively stimulate one GPCR downstream signaling pathway over others (biased signaling/functional selectivity) presents a major opportunity to develop more effective and safer medicines that selectively activate the desired therapeutic pathway while minimizing side effects by not activating undesired pathways. However, the structure-based design of such drugs is impeded by the lack of an atomic-level mechanistic understanding of biased signaling, a quintessential biological mechanism in its own right. The goal of this proposal is to 1. elucidate the molecular mechanism of biased signaling and 2. design biased ligands based on this insight that will serve as lead molecules for future drug development campaigns. The application to the serotonin 2A receptor, a pharmacologically highly important drug target for neuropsychiatric disorders, will have a major impact, as it will enable the rational design of a completely new generation of neuropsychiatric drugs with greater efficacy and fewer side effects. By combining state-of-the-art molecular simulations with complementary experimental approaches, this project bridges mechanistic insight and ligand design, and paves the way for the development of clinically useful therapeutics.

G蛋白偶联受体（GPCR）是人类膜蛋白中最大的一类，几乎控制着我们生理学的所有方面。超过三分之一的药物依赖于与GPCR的相互作用来治疗各种疾病，包括神经精神疾病，癌症和阿尔茨海默氏症。在细胞外信号分子结合后，GPCR改变其形状并偶联至细胞内转导蛋白，如G蛋白和抑制蛋白，其激活不同的细胞内信号级联。结合GPCR中的相同结合位点的某些分子可以选择性地刺激一种GPCR下游信号传导途径而不是其他信号传导途径（偏置信号传导/功能选择性）的发现提供了开发更有效和更安全的药物的主要机会，这些药物选择性地激活所需的治疗途径，同时通过不激活不需要的途径来最小化副作用。然而，这种药物的基于结构的设计受到缺乏对偏置信号传导的原子水平机械理解的阻碍，偏置信号传导本身就是一种典型的生物学机制。该提案的目标是1。阐明偏性信号传导的分子机制; 2.基于这一洞察设计偏向配体，将作为未来药物开发活动的先导分子。5-羟色胺2A受体是治疗神经精神疾病的一个非常重要的药物靶点，其应用将产生重大影响，因为它将使全新一代神经精神药物的合理设计具有更大的疗效和更少的副作用。通过将最先进的分子模拟与互补的实验方法相结合，该项目将机制洞察力和配体设计结合起来，为临床有用的治疗方法的开发铺平了道路。