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首页> 外文期刊>Egyptian Journal of Medical Human Genetics >Computational evaluation of small molecule inhibitors of RGS4 to regulate the dopaminergic control of striatal LTD
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Computational evaluation of small molecule inhibitors of RGS4 to regulate the dopaminergic control of striatal LTD

机译：RGS4小分子抑制剂调节纹状体LTD多巴胺能控制的计算评估

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Parkinson’s disease is a neurodegenerative disease which is the result of the degradation of the dopaminergic neurons in the substantia nigra pars compacta, leading to a disregulation of thalamocortical circuits. Traditional treatment involves the use of levodopa which increases the dopamine level in the striatum. There is a need for alternative non-dopamine therapy to prevent the side effects of the conventional drugs used. Recently small molecule inhibitors of RGS have become the prime candidates in studies related to regulating RGS by binding to its allosteric site and thus changing its structure. Through the docking studies we observed that these small molecule modulators of RGS4 make stable complexes with RGS4 when compared to native RGS4. The Gq(alpha)–RGS4–drug complexes are less stable. The increase in flexibility of the RGS4–drug complex could be the reason for the inability of the RGS4–drug complex to bind to the G protein. In our docking results, CCG63802 formed the most promising drug as a RGS4 inhibitor as it formed the most stable complex with RGS4 and also formed the least stable complex, Gq(alpha)–RGS4–CCG63802 complex. In our studies we evaluated the therapeutic potential of the small molecule inhibitors to provide a prospective treatment for Parkinson’s disease.
机译：帕金森氏病是一种神经退行性疾病，是黑质致密部中多巴胺能神经元降解的结果，导致丘脑皮质回路失调。传统治疗包括使用左旋多巴，左旋多巴可增加纹状体中的多巴胺水平。需要替代性的非多巴胺疗法以防止所用常规药物的副作用。最近，RGS的小分子抑制剂已成为与RGS通过结合其变构位点从而改变其结构来调节RGS有关的主要研究对象。通过对接研究，我们发现与天然RGS4相比，RGS4的这些小分子调节剂可与RGS4形成稳定的复合物。 Gq（α）–RGS4–药物复合物的稳定性较差。 RGS4 –药物复合物的灵活性增加可能是RGS4 –药物复合物无法结合G蛋白的原因。在我们的对接结果中，CCG63802成为RGS4抑制剂最有希望的药物，因为它与RGS4形成最稳定的复合物，并且还形成了最不稳定的复合物Gqα-RGS4-CCG63802复合物。在我们的研究中，我们评估了小分子抑制剂为帕金森氏病提供前瞻性治疗的潜力。

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