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无序蛋白会导致严重的药物副作用吗?

May disordered protein cause serious drug side effect?

作者信息

Tou Weng Ieong, Chen Calvin Yu-Chian

机构信息

School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan.

School of Medicine, College of Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Biotechnology, Asia University, Taichung, 41354, Taiwan; China Medical University Beigang Hospital, Yunlin, 65152, Taiwan; Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

出版信息

Drug Discov Today. 2014 Apr;19(4):367-72. doi: 10.1016/j.drudis.2013.10.020. Epub 2013 Oct 31.

Abstract

Insomnia is a self-reported disease where patients lose their ability to initiate and maintain sleep, leading to daytime performance impairment. Several drug targets to ameliorate insomnia symptoms have been discovered; however, these drug targets lead to serious side effects. Thus, we characterize the structural properties of these sleep-related receptors and the clock complex and discuss a possible drug design that will reduce side effects. Computational prediction shows that disordered property is shared. Over 30% of the structure of CLOCK, PER1/2/3, BMAL-1, muscarinic acetylcholine receptor-M1, melatonin receptor and casein kinase I are structurally disordered (the remaining proteins represent <30%). Investigations support the principle that the failures of insomnia drugs might be closely related to the protein architecture.

摘要

失眠是一种自我报告的疾病,患者失去启动和维持睡眠的能力,导致白天的功能受损。已经发现了几种改善失眠症状的药物靶点;然而,这些药物靶点会导致严重的副作用。因此,我们对这些与睡眠相关的受体和生物钟复合物的结构特性进行了表征,并讨论了一种可能减少副作用的药物设计。计算预测表明,无序特性是共有的。生物钟(CLOCK)、周期蛋白1/2/3(PER1/2/3)、脑和肌肉芳香烃受体核转位蛋白1(BMAL-1)、毒蕈碱型乙酰胆碱受体M1、褪黑素受体和酪蛋白激酶I超过30%的结构在结构上是无序的(其余蛋白质的无序结构占比小于30%)。研究支持这样的观点,即失眠药物的失效可能与蛋白质结构密切相关。

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