Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan.
Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Applied Science Private University, Amman 11931, Jordan.
Molecules. 2020 Dec 18;25(24):6003. doi: 10.3390/molecules25246003.
Aurora-A kinase plays a central role in mitosis, where aberrant activation contributes to cancer by promoting cell cycle progression, genomic instability, epithelial-mesenchymal transition, and cancer stemness. Aurora-A kinase inhibitors have shown encouraging results in clinical trials but have not gained Food and Drug Administration (FDA) approval. An innovative computational workflow named Docking-based Comparative Intermolecular Contacts Analysis (dbCICA) was applied-aiming to identify novel Aurora-A kinase inhibitors-using seventy-nine reported Aurora-A kinase inhibitors to specify the best possible docking settings needed to fit into the active-site binding pocket of Aurora-A kinase crystal structure, in a process that only potent ligands contact critical binding-site spots, distinct from those occupied by less-active ligands. Optimal dbCICA models were transformed into two corresponding pharmacophores. The optimal one, in capturing active hits and discarding inactive ones, validated by receiver operating characteristic analysis, was used as a virtual in-silico search query for screening new molecules from the National Cancer Institute database. A fluorescence resonance energy transfer (FRET)-based assay was used to assess the activity of captured molecules and five promising Aurora-A kinase inhibitors were identified. The activity was next validated using a cell culture anti-proliferative assay (MTT) and revealed a most potent lead molecule after 72 h of incubation, scoring IC values of 3.5-11.0 μM against PANC1 (pancreas), PC-3 (prostate), T-47D and MDA-MB-231 (breast)cancer cells, and showing favorable safety profiles (27.5 μM IC on fibroblasts). Our results provide new clues for further development of Aurora-A kinase inhibitors as anticancer molecules.
极光激酶 A 在有丝分裂中起着核心作用，异常激活通过促进细胞周期进程、基因组不稳定性、上皮-间充质转化和癌症干性促进癌症。极光激酶 A 抑制剂在临床试验中显示出令人鼓舞的结果，但尚未获得美国食品和药物管理局 (FDA) 的批准。应用了一种名为基于对接的比较分子间接触分析 (dbCICA) 的创新计算工作流程，旨在识别新型极光激酶 A 抑制剂-使用 79 种已报道的极光激酶 A 抑制剂来指定尽可能拟合极光激酶 A 激酶晶体结构活性部位结合口袋的最佳对接设置，在这个过程中，只有有效配体与关键结合部位接触，与活性较低的配体不同。将最优 dbCICA 模型转化为两个相应的药效团。最优模型在捕获活性命中物和排除非活性命中物方面通过接收者操作特征分析得到验证，可作为虚拟计算搜索查询，用于从国家癌症研究所数据库中筛选新分子。荧光共振能量转移 (FRET) 测定法用于评估捕获分子的活性，鉴定出 5 种有前途的极光激酶 A 抑制剂。随后使用细胞培养抗增殖测定法 (MTT) 验证活性，并在孵育 72 小时后发现最有效的先导分子，对 PANC1(胰腺)、PC-3(前列腺)、T-47D 和 MDA-MB-231(乳腺)癌细胞的 IC 值为 3.5-11.0 μM，显示出有利的安全性特征 (对成纤维细胞的 IC 为 27.5 μM)。我们的结果为进一步开发作为抗癌药物的极光激酶 A 抑制剂提供了新的线索。
