Structure-based design of targeted covalent inhibitors†,Chemical Society Reviews

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Structure-based design of targeted covalent inhibitors†
Chemical Society Reviews ( IF 40.4 ) Pub Date : 2018-04-05 00:00:00 , DOI: 10.1039/c7cs00220c
Richard Lonsdale _{1,

2,

3,

4,

5} , Richard A. Ward _{1,

2,

3,

4,

5}

Affiliation

Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non-covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach, and provide an overview of the current status of the field. We also describe some strategies and computational tools to enable successful covalent drug discovery.

中文翻译：

靶向共价抑制剂的基于结构的设计†

共价抑制是药物发现中快速发展的学科。偶然发现了许多历史上的共价抑制剂，由于潜在的毒性问题，这种作用机制通常被认为是不希望的。由于共价抑制显示出对先前鉴定非共价小分子抑制剂的努力失败的靶标的希望，因此最近的进展已经看到了这一前景的重大转变。靶向共价抑制剂（TCI）可以为药物发现科学家提供通过结合设计为共价结合至靶标特定位点的反应性官能团来提高小分子抑制剂的效价和/或选择性的能力。在本教程的复习中，我们介绍了共价抑制的更广泛概念，讨论了这种方法的潜在好处和挑战，并提供该字段的当前状态的概述。我们还描述了一些成功实现共价药物发现的策略和计算工具。

更新日期：2018-04-05

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