Protein–protein interactions (PPIs) are known to play an essential role between the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to regulate synapse function, emerging as a druggable interface for synaptopathies such as the fragile X syndrome (FXS). Recently, the phenothiazine FD44 has been identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. Here, we have integrated advanced experimental and computational studies to obtain important structural insights into Drosophila NCS-1/FD44 recognition to understand the basis of its affinity and specificity and generate improved PPI regulators. This has allowed the identification of a new small drug-like molecule, IGS-1.76, which efficiently inhibits the human NCS-1/Ric8a complex with improved binding potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different from FD44, shares the same mechanism of action and constitutes a new hit candidate for FXS.

中文翻译：

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用小吩噻嗪分子破译对神经元钙传感器1和鸟嘌呤交换因子Ric8a的抑制作用，以合理产生治疗性突触功能调节剂。

蛋白质间相互作用（PPI）在神经元钙传感器1（NCS-1）和鸟嘌呤交换因子Ric8a之间起着调节突触功能的重要作用，并逐渐成为诸如易碎X综合征等突触病的可治疗界面（ FXS）。最近，吩噻嗪FD44已被鉴定为该PPI的抑制剂，可降低FXS动物模型中异常高的突触数量并增强联想学习。在这里，我们集成了先进的实验和计算研究，以获取对果蝇的重要结构见解。NCS-1 / FD44识别可了解其亲和力和特异性的基础并生成改进的PPI调节剂。这样就可以鉴定出一种新的类似药物的小分子IGS-1.76，它可以有效抑制人NCS-1 / Ric8a复合物，并具有增强的结合力。果蝇NCS-1 / IGS-1.76复合物的晶体结构表明，这种新抑制剂尽管化学性质与FD44不同，但具有相同的作用机理，并构成了FXS的新候选药物。