In designing covalent kinase inhibitors (CKIs), the inclusion of electrophiles as attacking warheads demands careful choreography, ensuring not only their presence on the scaffold moiety but also their precise interaction with nucleophiles in the binding sites. Given the limited number of known electrophiles, exploring adjacent chemical space to broaden the palette of available electrophiles capable of covalent inhibition is desirable. Here, we systematically analyze the characteristics of warheads and the corresponding adjacent fragments for use in CKI design. We first collect all the released cysteine-targeted CKIs from multiple databases and create one CKI data set containing 16,961 kinase-inhibitor data points from 12,381 unique CKIs covering 146 kinases with accessible cysteines in their binding pockets. Then, we analyze this data set, focusing on the extended warheads (i.e., warheads + adjacent fragments)─including 30 common warheads and 1344 unique adjacent fragments. In so doing, we provide structural insights and delineate chemical properties and patterns in these extended warheads. Notably, we highlight the popular patterns observed within reversible CKIs for the popular warheads cyanoacrylamide and aldehyde. This study provides medicinal chemists with novel insights into extended warheads and a comprehensive source of adjacent fragments, thus guiding the design, synthesis, and optimization of CKIs.

中文翻译：

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探索开发半胱氨酸靶向共价激酶抑制剂的扩展弹头。


在设计共价激酶抑制剂 （CKI） 时，将亲电试剂作为攻击弹头需要仔细编排，不仅确保它们存在于支架部分上，而且确保它们与结合位点中的亲核试剂精确相互作用。鉴于已知亲电试剂的数量有限，探索相邻的化学空间以扩大能够共价抑制的可用亲电试剂的调色板是可取的。在这里，我们系统地分析了用于 CKI 设计的弹头和相应的相邻碎片的特性。我们首先从多个数据库中收集所有已释放的半胱氨酸靶向 CKI，并创建一个 CKI 数据集，其中包含来自 12,381 个独特 CKI 的 16,961 个激酶抑制剂数据点，涵盖 146 种激酶，其结合口袋中含有可接近的半胱氨酸。然后，我们分析了这个数据集，重点关注扩展弹头（即弹头 + 相邻碎片）——包括 30 个常见弹头和 1344 个独特的相邻碎片。在此过程中，我们提供了结构见解并描绘了这些扩展弹头的化学性质和模式。值得注意的是，我们重点介绍了在可逆 CKI 中观察到的常见弹头氰丙酰胺和醛的常见模式。这项研究为药物化学家提供了关于扩展弹头和相邻片段综合来源的新见解，从而指导 CKI 的设计、合成和优化。