Development of a novel fragment screening platform for G protein-Coupled Receptors

“G蛋白偶联受体（GPCR）是在细胞表面发现的蛋白质：它们检测细胞外的分子，从而激活介导细胞反应的内部信号通路。GPCR是最重要的人类药物靶点类别之一，并且由25-30%的市售药物解决。许多已知具有疾病相关性的GPCR仍然未被破坏，突出了这一目标群体在寻找新药方面的持续重要性。从历史上看，研究GPCR的方法在识别和分析调节其功能的化学物质方面非常成功。然而，这些经验方法往往发现对所需靶点仅具有部分选择性的化合物，因为它们提供的信息不够精确，无法推动合理的药物设计，使药物具有高度特异性。最近已经表明，制造一些GPCR的突变形式使它们足够稳定，可以使用结构和生物物理方法来设计更具选择性的药物，并解锁这类传统上不可药物化的靶标。但这是一项艰巨而漫长的任务，需要针对每个目标进行广泛的方法开发。Domainex采用了一种新的方法，使用称为微尺度热泳（MST）的生物物理技术启动药物发现项目。该提案将测试在GPCR上使用这种方法的可行性，以建立一个通用平台，使任何纯化的GPCR都能够工作，而不需要稳定突变。我们将使用一种在英国大学开发的新方法来稳定GPCR。如果成功的话，这个项目将为Domainex提供一种新的服务给潜在的客户。这将为公司带来新的收入，并促进我们客户的研究项目，这意味着更好的药物将更快地到达患者手中。"

"G-protein coupled receptors (GPCRs) are proteins found on the surface of cells: they detect molecules outside the cell and consequently activate internal signalling pathways that mediate cellular responses. GPCRs are one of the most important human drug target classes, and are addressed by 25-30% of marketed drugs. Many GPCRs that are known to have disease relevance remain undrugged, highlighting the ongoing importance of this target group in the search for new medicines.Historically, methods of studying GPCRs have been very successful at identifying and profiling chemicals that modulate their function. However, these empirical approaches have tended to find compounds that are only partially selective for the desired target, because they give insufficiently precise information to drive rational drug design towards highly-specific agents. Recently it has been shown that making mutated forms of some GPCRs makes them stable enough to use structural and biophysical methods that can allow the design of more selective drugs, and unlock traditionally undruggable targets of this class. But this is a difficult and lengthy task requiring extensive method development for each individual target.Domainex has embraced a new method for starting drug discovery projects using a biophysical technique called MicroScale Thermophoresis (MST). This proposal will test the feasibility of using this approach on GPCRs, in order to establish a generic platform that would enable work any purified GPCR without the need for stabilising mutations. We will use a new method developed in a UK university to stabilise the GPCR.If successful, this project will lead to a new service that Domainex can offer to prospective clients. This will provide the Company with new revenues, and facilitate our clients' research projects meaning that better drugs will get to patients, faster."