New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design.,Biochemistry

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New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design.
Biochemistry ( IF 2.9 ) Pub Date : 2019-04-24 , DOI: 10.1021/acs.biochem.9b00293
Sneha Ray ₁ , Andrew S Murkin ₁

Affiliation

Covalent inhibitors are experiencing a growing resurgence in drug design and are an increasingly useful tool in molecular biology. The ability to attach inhibitors to their targets by a covalent linkage offers pharmacodynamic and pharmacokinetic advantages, but this can also be a liability if undesired off-target reactions are not mitigated. The discovery of new electrophilic groups that react selectively with specific amino acid residues is therefore highly desirable in the design of targeted covalent inhibitors (TCIs). Additionally, the ability to control the reactivity through exploitation of the target enzyme's machinery, as in mechanism-based inhibitors (MBIs), greatly benefits from the discovery of new strategies. This Perspective showcases recent advances in electrophile development and their application in TCIs and MBIs, exhibiting high selectivity for their targets.

中文翻译：

基于机理和目标共价抑制剂设计的新亲电试剂和策略。

共价抑制剂在药物设计中正逐渐兴起，并且在分子生物学中已成为越来越有用的工具。通过共价键将抑制剂附着于其靶标的能力提供了药效学和药代动力学优势，但是如果不希望的脱靶反应没有得到缓解，这也可能是一个责任。因此，在设计目标共价抑制剂（TCI）时非常需要发现可以与特定氨基酸残基选择性反应的新亲电基团。此外，如基于机理的抑制剂（MBI）中一样，通过利用目标酶的机制来控制反应性的能力，也将从发现新策略中受益匪浅。本透视图展示了亲电子试剂开发的最新进展及其在TCI和MBI中的应用，

更新日期：2019-11-18

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