生物物理方法促进atp结合盒蛋白的计算药物发现。

International Journal of Medicinal Chemistry Pub Date : 2017-01-01 Epub Date: 2017-03-19 DOI:10.1155/2017/1529402
Steven V Molinski, Zoltán Bozóky, Surtaj H Iram, Saumel Ahmadi
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引用次数: 6

摘要

尽管膜蛋白代表了大多数治疗相关的药物靶点,但这类蛋白的原子分辨率结构的可用性受到限制。这些多体转运体、受体和通道的生物物理性质阻碍了结构表征,而最近体外技术的创新旨在减轻这些挑战。其中一类膜蛋白,atp结合盒(ABC)超家族,在整个人体中广泛表达,是正常生理和突变时致病所必需的,但在蛋白质数据库中缺乏足够的结构表示。然而,最近生物物理技术的改进(例如,冷冻电子显微镜)使得以前“难以研究”的ABC蛋白能够以高分辨率进行表征,从而深入了解分子作用机制以及揭示治疗设计的新药物位点。这些新的进展为计算方法(例如,虚拟筛选,分子动力学模拟和基于结构的药物设计)提供了充足的机会,以催化发现新的小分子疗法,这些疗法可以很容易地从计算机转化为实验台,随后转化为患者的床边。在这篇综述中,我们探讨了生物物理方法的最新进展以及成熟的计算机技术对由功能失调的ABC蛋白引起的疾病的药物开发的应用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Biophysical Approaches Facilitate Computational Drug Discovery for ATP-Binding Cassette Proteins.

Although membrane proteins represent most therapeutically relevant drug targets, the availability of atomic resolution structures for this class of proteins has been limited. Structural characterization has been hampered by the biophysical nature of these polytopic transporters, receptors, and channels, and recent innovations to in vitro techniques aim to mitigate these challenges. One such class of membrane proteins, the ATP-binding cassette (ABC) superfamily, are broadly expressed throughout the human body, required for normal physiology and disease-causing when mutated, yet lacks sufficient structural representation in the Protein Data Bank. However, recent improvements to biophysical techniques (e.g., cryo-electron microscopy) have allowed for previously "hard-to-study" ABC proteins to be characterized at high resolution, providing insight into molecular mechanisms-of-action as well as revealing novel druggable sites for therapy design. These new advances provide ample opportunity for computational methods (e.g., virtual screening, molecular dynamics simulations, and structure-based drug design) to catalyze the discovery of novel small molecule therapeutics that can be easily translated from computer to bench and subsequently to the patient's bedside. In this review, we explore the utility of recent advances in biophysical methods coupled with well-established in silico techniques towards drug development for diseases caused by dysfunctional ABC proteins.

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期刊介绍: International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis. International Journal of Medicinal Chemistry is a peer-reviewed, Open Access journal that publishes original research articles as well as review articles in all areas of chemistry associated with drug discovery, design, and synthesis.
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