LIMES Program Unit Chemical Biology and Medicinal Chemistry, Department of Life Science Informatics, B-IT, Rheinische Friedrich-Wilhelms-Universität, Friedrich-Hirzebruch-Allee 5/6, D-53115 Bonn, Germany.
Molecules. 2023 Aug 1;28(15):5805. doi: 10.3390/molecules28155805.
In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in allosteric PKIs (APKIs), which are expected to have high kinase selectivity. In addition, as compounds acting by covalent mechanisms experience a renaissance in drug discovery, there is also increasing interest in covalent PKIs (CPKIs). There are various reasons for this increasing interest such as the anticipated high potency, prolonged residence times compared to non-competitive PKIs, and other favorable pharmacokinetic properties. Due to the popularity of PKIs for therapeutic intervention, large numbers of PKIs and large volumes of activity data have accumulated in the public domain, providing a basis for large-scale computational analysis. We have systematically searched for CPKIs containing different reactive groups (warheads) and investigated their potency and promiscuity (multi-PK activity) on the basis of carefully curated activity data. For seven different warheads, sufficiently large numbers of CPKIs were available for detailed follow-up analysis. For only three warheads, the median potency of corresponding CPKIs was significantly higher than of non-covalent PKIs. However, for CKPIs with five of seven warheads, there was a significant increase in the median potency of at least 100-fold compared to PKI analogues without warheads. However, in the analysis of multi-PK activity, there was no general increase in the promiscuity of CPKIs compared to non-covalent PKIs. In addition, we have identified 29 new APKIs in X-ray structures of PK-PKI complexes. Among structurally characterized APKIs, 13 covalent APKIs in complexes with five PKs are currently available, enabling structure-based investigation of PK inhibition by covalent-allosteric mechanisms.
在药物发现中，蛋白激酶抑制剂（PKIs）作为不同治疗领域的候选药物受到了深入研究。虽然 ATP 结合位点的非共价 PKIs 一直是蛋白激酶（PK）药物发现的焦点，但近年来，变构 PKIs（APKIs）的兴趣日益增加，因为它们有望具有较高的激酶选择性。此外，由于共价机制作用的化合物在药物发现中重新受到关注，因此对共价 PKIs（CPKIs）的兴趣也在增加。这种兴趣增加的原因有很多，例如预期的高效力、与非竞争性 PKIs 相比延长的停留时间以及其他有利的药代动力学特性。由于 PKIs 常用于治疗干预，因此在公共领域积累了大量的 PKIs 和大量的活性数据，为大规模的计算分析提供了基础。我们系统地搜索了含有不同反应基团（弹头）的 CPKIs，并根据精心整理的活性数据研究了它们的效力和混杂性（多 PK 活性）。对于七种不同的弹头，有足够数量的 CPKIs 可用于详细的后续分析。对于只有三种弹头，相应的 CPKIs 的中位数效力明显高于非共价 PKIs。然而，对于七种弹头中的五种 CPKIs，与没有弹头的 PKI 类似物相比，其效力中位数至少增加了 100 倍。然而，在多 PK 活性分析中，与非共价 PKIs 相比，CPKIs 的混杂性并没有普遍增加。此外，我们在 PK-PKI 复合物的 X 射线结构中鉴定了 29 种新的 APKIs。在结构表征的 APKIs 中，目前有 13 种与五种 PK 结合的共价 APKIs，这使得可以基于结构研究共价变构机制对 PK 抑制的作用。
