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首页> 外文期刊>Journal of Medicinal Chemistry >Modulating G-protein coupled receptor/G-protein signal transduction by small molecules suggested by virtual screening
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Modulating G-protein coupled receptor/G-protein signal transduction by small molecules suggested by virtual screening

机译：虚拟筛选提示小分子调节G蛋白偶联受体/ G蛋白信号转导

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Modulation of interactions between activated GPCRs (G-protein coupled receptors) and the intracellular (IC) signal transducers, heterotrimeric G-proteins, is an attractive, yet essentially unexplored, paradigm for treatment of certain diseases. Regulating downstream signaling for treatment of congenital diseases due to constitutively active GPCRs, as well as tumors where GPCRs are often overexpressed, requires the development of new methodologies. Modeling, experimental data, docking, scoring, and experimental testing (MEDSET) was developed to discover inhibitors that target the IC loops of activated GPCRs. As proof-of-concept, MEDSET developed and utilized a model of the interface between photoactivated rhodopsin (R*) and transducin (Gt), its G-protein. A National Cancer Institute (NCI) Compound library was screened to identify compounds that bound at the interface between R* and its G-protein. High-scoring compounds from this virtual screen were obtained and tested experimentally for their ability to stabilize R* and prevent Gt from bindin, to V. Several compounds that modulate signal transduction have been identified.
机译：激活的GPCR（G蛋白偶联受体）与细胞内（IC）信号转导子（异源三聚G蛋白）之间相互作用的调节是治疗某些疾病的一种有吸引力的方法，但基本上尚未开发。调节下游信号以治疗由于组成性活性GPCR引起的先天性疾病以及GPCR经常过表达的肿瘤，需要开发新的方法。开发了模型，实验数据，对接，评分和实验测试（MEDSET），以发现针对活化GPCR的IC环的抑制剂。作为概念验证，MEDSET开发并利用了光活化视紫红质（R *）和其G蛋白转导素（Gt）之间的界面模型。筛选了美国国家癌症研究所（NCI）的化合物文库，以鉴定与R *及其G蛋白之间的界面结合的化合物。从该虚拟屏幕中获得了高分化合物，并通过实验测试了它们稳定R *并阻止Gt与V结合的能力。已经发现了几种调节信号转导的化合物。

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