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基于坎普托素的亲药物与人体基酶2结合的In Silico研究

Frank Beierlein^1,2, Anselm H C Horn^2,3, Heinrich Sticht³

¹Department for Chemistry and Pharmacy, Computer Chemistry Center, Friedrich-Alexander University Erlangen Nürnberg (FAU), Nägelsbachstraße 25, 91052 Erlangen, Germany.

|February 24, 2024

概括

研究人员研究了坎普托素子前药物,以评估其癌症化疗特异性. 分子模拟表明,这些前药物不太可能被人类的碳素化酶2化,这表明在健康组织中脱药物释放的风险很低.

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.
计算化学计算化学

背景情况:

支持药物提供向化疗,通过在癌症部位释放活性化合物来减少副作用.
雌激素前药物通过水解被激活,但正常组织中由氧乙酶的非特异激活是令人担忧的.
坎普托塞辛是一种拓聚酶I抑制剂,是一种潜在的抗癌药物,其子前药物需要仔细评估以获得向的输送.

研究的目的:

为了研究不同大小的坎普托塞辛子前药物与人体氧乙酶2 (HCE2) 的结合方式.
评估通过HCE2.2对这些前药物的水解和脱激活潜力.
为了比较坎普托素前药物的结合和水解潜力,与已知的HCE2基质, irinotekan.

主要方法:

分子对接模拟以确定HCE2活性部位内的前药物的结合姿势.
分子动力学模拟,以分析在有限温度的溶剂环境中的酶-连接体复合物的灵活性和稳定性.
结合相互作用的比较和潜在的水解竞争的姿势与 irinotcan.

主要成果:

所有三种研究的坎普托塞辛子子前药物都能与HCE2结合,但不是在水解的最佳姿势下.
在最初的质子转移后,观察到一种与反应物相匹配的位,表明酶激活.
动态模拟显示,在生理条件下,前药物不太可能被HCE2化.

结论:

被研究的坎普托塞辛 Ester 预药物在正常组织中表现出 HCE2 发生不良水解的低风险.
动态模拟对于准确评估除了静态对接模型之外的酶-连接体相互作用至关重要.
这些发现支持开发具有在癌症化疗中提高特异性的坎普托塞辛子前药的潜力.

关键词:

在Camptoothecin的营地里.停靠的对接方式同质模型的同质模型.人类的碳酸酶.分子动力学模拟,分子动力学模拟支持毒品的支持者.

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