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Expanding the Armory: Predicting and Tuning Covalent Warhead Reactivity
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-11-21 00:00:00 , DOI: 10.1021/acs.jcim.7b00553 Richard Lonsdale 1 , Jonathan Burgess 1 , Nicola Colclough 1 , Nichola L. Davies 1 , Eva M. Lenz 1 , Alexandra L. Orton 1 , Richard A. Ward 1
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2017-11-21 00:00:00 , DOI: 10.1021/acs.jcim.7b00553 Richard Lonsdale 1 , Jonathan Burgess 1 , Nicola Colclough 1 , Nichola L. Davies 1 , Eva M. Lenz 1 , Alexandra L. Orton 1 , Richard A. Ward 1
Affiliation
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Targeted covalent inhibition is an established approach for increasing the potency and selectivity of potential drug candidates, as well as identifying potent and selective tool compounds for target validation studies. It is evident that identification of reversible recognition elements is essential for selective covalent inhibition, but this must also be achieved with the appropriate level of inherent reactivity of the reactive functionality (or “warhead”). Structural changes that increase or decrease warhead reactivity, guided by methods to predict the effect of those changes, have the potential to tune warhead reactivity and negate issues related to potency and/or toxicity. The half-life to adduct formation with glutathione (GSH t1/2) is a useful assay for measuring the reactivity of cysteine-targeting covalent warheads but is limited to synthesized molecules. In this manuscript we assess the ability of several experimental and computational approaches to predict GSH t1/2 for a range of cysteine targeting warheads, including a novel method based on pKa. Furthermore, matched molecular pairs analysis has been performed against our internal compound collection, revealing structure–activity relationships between a selection of different covalent warheads. These observations and methods of prediction will be valuable in the design of new covalent inhibitors with desired levels of reactivity.
中文翻译：
扩展军械库：预测和调整共价战斗部的反应性
靶向共价抑制是一种建立的方法，可用于提高潜在候选药物的效力和选择性，以及确定用于目标验证研究的有效和选择性工具化合物。显然，可逆识别元件的识别对于选择性共价抑制是必不可少的，但这也必须通过适当的反应性官能团（或“战斗部”）固有反应性来实现。在预测这些变化影响的方法的指导下，增加或降低弹头反应性的结构变化具有调整弹头反应性和消除与效能和/或毒性有关的问题的潜力。谷胱甘肽加合物形成的半衰期（GSH t 1/2）是用于测量靶向半胱氨酸的共价战斗部的反应性的有用测定法，但仅限于合成分子。在本手稿中，我们评估了多种实验和计算方法预测一系列半胱氨酸靶向战斗部的GSH t 1/2的能力，包括基于p K a的新方法。此外，针对我们的内部化合物集合进行了匹配的分子对分析，揭示了不同共价战斗部之间的构效关系。这些观察结果和预测方法在设计具有所需反应性水平的新共价抑制剂时将具有重要价值。
更新日期：2017-11-22
中文翻译：
扩展军械库：预测和调整共价战斗部的反应性
靶向共价抑制是一种建立的方法，可用于提高潜在候选药物的效力和选择性，以及确定用于目标验证研究的有效和选择性工具化合物。显然，可逆识别元件的识别对于选择性共价抑制是必不可少的，但这也必须通过适当的反应性官能团（或“战斗部”）固有反应性来实现。在预测这些变化影响的方法的指导下，增加或降低弹头反应性的结构变化具有调整弹头反应性和消除与效能和/或毒性有关的问题的潜力。谷胱甘肽加合物形成的半衰期（GSH t 1/2）是用于测量靶向半胱氨酸的共价战斗部的反应性的有用测定法，但仅限于合成分子。在本手稿中，我们评估了多种实验和计算方法预测一系列半胱氨酸靶向战斗部的GSH t 1/2的能力，包括基于p K a的新方法。此外，针对我们的内部化合物集合进行了匹配的分子对分析，揭示了不同共价战斗部之间的构效关系。这些观察结果和预测方法在设计具有所需反应性水平的新共价抑制剂时将具有重要价值。
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