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通过分子模拟探索激酶抑制剂的药物重新定位可能性

Qing-Xin Wang¹, Jiao Cai¹, Zi-Jun Chen¹

¹National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, 210023, Nanjing, Jiangsu, China.

Molecular informatics

|July 20, 2024

概括

这项研究引入了一种具有成本效益的in silico方法,用于预测激酶抑制剂 (KI) 药物重新定位. 该方法成功地通过交叉对接分析识别了现有知识产权,这些知识产权有可能用于新的治疗应用.

科学领域:

生物化学生物化学
药理学药理学是指药理学的学科.
计算生物学计算生物学

背景情况:

激酶是参与细胞信号的关键酶,调节各种基质的酸化.
在酶中保留的ATP结合口袋对选择性抑制剂设计构成挑战,但为药物重新定位提供了机会.
激酶抑制剂 (KIs) 在治疗由异常激酶活性驱动的疾病中至关重要.

研究的目的:

开发和验证一种具有成本效益的in silico方法,用于预测激酶抑制剂的药物重新定位.
为了确定合适的酶超级家族和特定的酶抑制剂进行重新定位.
评估使用计算方法用于酶抑制剂重定位的可行性.

主要方法:

创建一个全面的激酶抑制剂 (KI) 数据库 (278个KI,1834个生物活性点) 和一个激酶结构数据库 (357个激酶,DFG动机分类).
在KI和酶结构之间执行交叉对接模拟.
对对接分数与实验生物活性数据进行比较分析,以确定适合重新定位的超级家族.

主要成果:

根据交叉对接分析,确定了非典型的,TK和TKL激酶超级家族是适合药物重新定位的.
奥尔韦马提尼布,拉帕提尼布和阿贝马西克利布对AKT-PI3K-mTOR通路 (IC50值:3.3,3.2,5.8μM) 显示出酶活性.
这些化合物还在细胞测定中显示出显著的抗瘤活性 (IC50值:0.2,1.2,0.6μM),验证了in silico预测.

结论:

通过交叉对接分析进行in silico预测是一种可行且具有成本效益的策略,用于识别酶抑制剂药物重新定位的机会.
该研究通过实验性酶和细胞分析成功验证了计算预测.
这种方法可以加速发现现有的激酶抑制剂的新疗法应用.

关键词:

这是一种抗癌药物.数据分析数据分析数据分析药物重新定位药物重新定位激酶抑制剂激酶抑制剂分子模拟分子模拟

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