Hong Lin, Sklar Larry A
Department of Pathology, The University of New Mexico Albuquerque, NM, USA ; Center for Molecular Discovery, The University of New Mexico Albuquerque, NM, USA.
Department of Pathology, The University of New Mexico Albuquerque, NM, USA ; Center for Molecular Discovery, The University of New Mexico Albuquerque, NM, USA ; Cancer Center, The University of New Mexico Albuquerque, NM, USA.
Front Mol Neurosci. 2014 Jun 5;7:52. doi: 10.3389/fnmol.2014.00052. eCollection 2014.
Neurological diseases have placed heavy social and financial burdens on modern society. As the life expectancy of humans is extended, neurological diseases, such as Parkinson's disease, have become increasingly common among senior populations. Although the enigmas of Parkinson's diseases await resolution, more vivid pictures on the cause, progression, and control of the illness are emerging after years of research. On the molecular level, GTPases are implicated in the etiology of Parkinson's disease and are rational pharmaceutical targets for their control. However, targeting individual GTPases, which belong to a superfamily of proteins containing multiple members with a conserved guanine nucleotide binding domain, has proven to be challenging. In contrast, pharmaceutical pursuit of inhibition of kinases, which constitute another superfamily of proteins with more than 500 members, has been fairly successful. We reviewed the breakthroughs in the history of kinase drug discovery to provide guidance for the GTPase field. We summarize recent progress made in the regulation of GTPase activity. We also present an efficient and cost effective approach to drug screening, which uses multiplex flow cytometry and mixture-based positional scanning libraries. These methods allow simultaneous measurements of both the activity and the selectivity of the screened library. Several GTPase activator clusters were identified which showed selectivity against different GTPase subfamilies. While the clusters need to be further deconvoluted to identify individual active compounds, the method described here and the structure information gathered create a foundation for further developments to build upon.
神经疾病给现代社会带来了沉重的社会和经济负担。随着人类预期寿命的延长，帕金森病等神经疾病在老年人群中变得越来越普遍。尽管帕金森病的谜团有待解开，但经过多年研究，关于该疾病的病因、进展和控制方面越来越清晰。在分子水平上，GTP酶与帕金森病的病因有关，是控制该疾病的合理药物靶点。然而，针对属于含有多个成员且具有保守鸟嘌呤核苷酸结合结构域的蛋白质超家族的单个GTP酶，已证明具有挑战性。相比之下，对构成另一个拥有500多个成员的蛋白质超家族的激酶进行药物抑制的研究相当成功。我们回顾了激酶药物发现史上的突破，为GTP酶领域提供指导。我们总结了GTP酶活性调节方面的最新进展。我们还提出了一种高效且经济有效的药物筛选方法，该方法使用多重流式细胞术和基于混合物的位置扫描文库。这些方法允许同时测量筛选文库的活性和选择性。鉴定出了几个对不同GTP酶亚家族具有选择性的GTP酶激活剂簇。虽然这些簇需要进一步解卷积以鉴定单个活性化合物，但本文所述方法和收集到的结构信息为进一步发展奠定了基础。
