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G-protein-coupled receptor-focused drug discovery using a target class platform approach.

机译：使用目标类别平台方法进行的G蛋白偶联受体相关药物发现。

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摘要

In recent years, several large pharmaceutical companies have taken a novel approach to drug discovery biology and chemistry in that they channel their efforts with respect to particular target classes, such as G-protein-coupled receptors (GPCRs), toward dedicated, specialized teams. Benefits of such an organizational structure are the prospects of establishing several target-family-specific experimental techniques and skill sets, thereby enabling a comprehensive functional profiling of drug candidates in different pharmacological respects. In this context, the recently increased number of reports on GPCR ligand-biased signaling has further spurred the efforts in the pharmaceutical industry toward broader biological characterization of the test compounds, for example employing high-content screening to analyze different GPCR ligand-induced signaling pathways. The knowledge of the disease-relevant functional properties of the small molecule GPCR ligands enables target-specific chemical optimization and GPCR-subclass-directed library design. In the case of GPCRs, where little--although at present slowly expanding--structural information on the targets is available, the modeling of GPCR structures crucially depends on biological validation (typically supported by site-directed mutagenesis of the GPCR ligand binding site). In this review, we aim to recapitulate efforts in the pharmaceutical industry to address GPCR-directed drug discovery in a target-class-directed platform approach: establishing GPCR-specific biological assay panels and creating computational chemistry methods for finding and optimizing small molecules modulating the activity of GPCRs.
机译：近年来，几家大型制药公司采用了一种新颖的药物发现生物学和化学方法，将他们针对特定目标类别（例如G蛋白偶联受体（GPCR））的努力引向了专门的专业团队。这种组织结构的好处是建立几种针对特定目标家庭的实验技术和技能集的前景，从而可以对不同药理学方面的候选药物进行全面的功能分析。在这种情况下，最近有关GPCR配体偏向信号转导的报道数量越来越多，这进一步刺激了制药行业朝着更广泛的测试化合物生物学表征的努力，例如采用高含量筛选来分析不同的GPCR配体诱导的信号通路。 。小分子GPCR配体与疾病相关的功能特性的知识使目标特定的化学优化和GPCR子类指导的文库设计成为可能。在GPCR的情况下，几乎没有（尽管目前正在缓慢扩展）关于靶标的结构信息，GPCR结构的建模至关重要地取决于生物学验证（通常由GPCR配体结合位点的定向诱变支持） 。在本综述中，我们旨在概述制药行业在目标类指导的平台方法中解决GPCR指导的药物发现的努力：建立特定于GPCR的生物检测面板，并创建计算化学方法以发现和优化调节小分子的药物。 GPCR的活性。

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