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化学进展 2014, Vol. 26 Issue (01): 193-202 DOI: 10.7536/PC130612 前一篇   后一篇

• 综述与评论 •

甲状腺结合前清蛋白的理论研究

赵丽君, 雷鸣*   

  1. 北京化工大学理学院 现代药物研究所 化工资源有效利用国家重点实验室 北京 100029
  • 收稿日期:2013-06-01 修回日期:2013-09-01 出版日期:2014-01-15 发布日期:2013-11-08
  • 通讯作者: 雷鸣，e-mail：leim@mail.buct.edu.cn E-mail:leim@mail.buct.edu.cn
  • 基金资助:

    国家自然科学基金项目（No. 20703003，21072018，21373023）资助

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Computational Chemical Studies on Transthyretin

Zhao Lijun, Lei Ming*   

  1. State Key Laboratory of Chemical Resource Engineering, Institute of Materia Medica, College of Science, Beijing University of Chemical Technology, Beijing 100029, China
  • Received:2013-06-01 Revised:2013-09-01 Online:2014-01-15 Published:2013-11-08
  • Supported by:

    The work was supported by the National Natural Science Foundation of China (No. 20703003, 21072018, 21373023)

甲状腺结合前清蛋白TTR是一种具有重要生理功能的蛋白质，它是约30种与淀粉样疾病相关的非同源蛋白中的一种。与TTR相关的淀粉样疾病主要有：家族淀粉化心肌疾病，家族淀粉化神经系统疾病，老年系统性淀粉样病变，以及中枢神经系统选择性淀粉化疾病等。这些疾病是由TTR四聚体解聚过程中错误折叠形成cross-β-sheet结构形态的淀粉样纤维所导致。本文介绍了TTR的生理功能及结构特征，并综述了到目前为止用分子动力学模拟、分子对接和定量构效关系等方法在研究TTR淀粉样机理及TTR和小分子相互作用过程中的计算化学研究成果，为基于TTR结构的TTR淀粉样抑制剂药物分子的设计和筛选提供有力参考。

关键词： 甲状腺结合前清蛋白, 分子动力学模拟, 分子对接, 定量构效关系, 药物筛选

Transthyretin (TTR) is a tetramer protein, and it is one of around 30 non-homologic amyloidogenic human proteins related to amyloid diseases. The diseases related to TTR amyloid include familial amyloid cardiomyopathy (FAC), familial amyloid polyneuropathy (FAP), senile systemic amyloidosis (SSA), and central nervous system-selective amyloidosis (CNSA). These diseases are proposed to be due to the formation of TTR amyloid and the construction of cross-β -sheet subunit via TTR misfolding. In this review, we describe the physiological characteristics and structural features of TTR, and summarize computational studies on TTR using molecular dynamics simulation, molecular docking and quantitative structure-activity relationships. These computational chemical studies demonstrate possible mechanisms of TTR amyloid formation and the binding abilities of small molecules and TTR, which may provide insights to discover and screen new inhibitors preventing TTR from misfolding.

Contents
1 Introduction
1.1 Physiological function and structural charac-teristics of TTR
1.2 Diseases caused by misfolding of TTR
1.3 Mechanisms of amyloid formation
1.4 Treatment of amyloid diseases
2 Molecular dynamic simulation on TTR
2.1 The mechanisms of TTR amyloid formation
2.2 The binding modes of small molecules with TTR
3 Molecular docking studies on TTR
4 Quantitative structure-activity relationship studies on TTR
5 Outlook

Key words: transthyretin, molecular dynamics simulation (MD), molecular docking, quantitative structure-activity relationship (QSAR), drug screening

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摘要

甲状腺结合前清蛋白的理论研究