Direct targeting of intracellular Gα subunits of G protein‐coupled receptors by chemical tools is a challenging task in current pharmacological studies and in the development of novel therapeutic approaches. In this study we analyzed novel FR900359‐based analogs from natural sources, synthetic cyclic peptides, as well as all so‐far known G_qα inhibitors in a comprehensive study to devise a strategy for the elucidation of characteristics that determine interactions with and inhibition of G_q in the specific FR/YM‐binding pocket. Using 2D NMR spectroscopy and molecular docking we identified unique features in the macrocyclic structures responsible for binding to the target protein correlating with inhibitory activity. While all novel compounds were devoid of effects on G_i and G_s proteins, no inhibitor surpassed the biological activity of FR. This raises the question of whether depsipeptides such as FR already represent valuable chemical tools for specific inhibition of G_q and, at the same time, are suitable natural lead structures for the development of novel compounds to target Gα subunits other than G_q.

中文翻译：

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基于计算和结构-活性研究的FR900359衍生Gqα抑制剂的破译特异性决定因素

化学工具直接靶向G蛋白偶联受体的细胞内Gα亚基是当前药理学研究和新型治疗方法开发中的一项艰巨任务。在这项研究中，我们分析了来自天然来源的，合成的环肽，以及所有的迄今为止已知G新颖的基于FR900359-类似物_q α中的综合研究抑制剂，设计一种用于决定相互作用与和抑制特性的阐明的策略特定FR / YM装订袋中的G _q。使用2D NMR光谱学和分子对接，我们确定了大环结构中与结合抑制活性相关的靶蛋白结合的独特特征。虽然所有新化合物都没有对G _i产生影响和G _s蛋白，没有任何抑制剂能超过FR的生物学活性。这就提出了这样的问题，即脱肽肽（例如FR）是否已经代表了对_Gq进行特异性抑制的有价值的化学工具，并且同时又是合适的天然先导结构，用于开发靶向_Gq以外的Gα亚基的新型化合物。