New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design
New Electrophiles and Strategies for Mechanism-Based and Targeted Covalent Inhibitor Design
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DOI：
10.1021/acs.biochem.9b00293
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发表时间：
2019-12-31
期刊：
影响因子：
2.9
通讯作者：
Murkin, Andrew S.
中科院分区：
文献类型：
--
作者：
Ray, Sneha;Murkin, Andrew S.
共价抑制剂在药物设计中正经历着越来越多的复兴，并成为分子生物学中越来越有用的工具。通过共价键将抑制剂连接到靶点的能力提供了药效学和药动学方面的优势，但如果不能减轻不希望发生的靶外反应，这也可能是一种不利因素。因此，在靶向共价抑制剂(TCI)的设计中，发现与特定氨基酸残基选择性反应的新的亲电基团是非常可取的。此外，通过利用靶酶的机制来控制反应活性的能力，如基于机制的抑制剂(MBIS)，极大地得益于新策略的发现。这一视角展示了电泳剂开发的最新进展及其在TCI和MBIS中的应用，显示出对其目标的高选择性。
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.