激酶是一类控制各种底物磷酸化的酶，在生理和病理过程中都至关重要。尽管其保守的 ATP 结合口袋对实现选择性提出了挑战，但这一特征为激酶抑制剂 (KI) 的药物重新定位提供了机会。这项研究通过分析交叉对接结果，提出了一种具有成本效益的 KI 药物重新定位计算机预测方法。我们建立了KI数据库（278个独特的KI，1834个生物活性数据点）和激酶数据库（按DFG基序分类的357个激酶结构）用于进行交叉对接。对接分数和报告的实验生物活性的比较分析表明，Atropic、TK 和 TKL 超家族适合药物重新定位。在这些激酶超家族中，Olverematinib、Lapatinib 和 Abemaciclib 在我们重点关注的 AKT-PI3K-mTOR 通路中显示出酶活性，IC50 值为 3.3、3.2 和 5.8μM。进一步的细胞测定显示肿瘤细胞中的 IC50 值为 0.2、1.2 和 0.6 μM。预测和验证之间的一致结果表明，通过计算机方法重新定位 KI 是可行的。© 2024 Wiley-VCH GmbH。

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 μM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 μM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.© 2024 Wiley-VCH GmbH.