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对HDAC-连接体复合体的分子动力学模拟,旨在设计新的抗癌化合物

Varun Dewaker^1,2, Yenamandra S Prabhakar¹

¹Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India.

Current topics in medicinal chemistry

|October 2, 2023

概括

定量结构-活性关系 (QSAR) 研究和分子动力学 (MD) 模拟有助于设计新的抗癌药物. MD模拟解码相互作用,促进开发用于癌症治疗的新型希斯脱乙酶 (HDAC) 抑制剂.

科学领域:

计算化学和药物发现
药品化学和药理学药品化学和药理学

背景情况:

定量结构-活性关系 (QSAR) 研究在20世纪60年代出现,以将化合物结构与生物活性相关联.
计算能力的进步扩大了QSAR,并引入了新技术,如分子动力学 (MD) 模拟用于药物设计.
基因组脱乙酶 (HDACs) 是关键的表观遗传调节剂,也是癌症治疗的重要标.

研究的目的:

审查HDAC抑制剂作为抗癌剂的建模研究.
突出MD模拟在直接药物设计中的实用性.
讨论一种基于碎片的方法来设计使用MD模拟数据的新型HDAC8和HDAC2抑制剂.

主要方法:

使用MD模拟来分析蛋白质 - 配体复杂动力学和分子间相互作用.
从MD轨迹中提取连接体碎片的相互作用能量.
应用基于片段的方法来设计基于MD模拟见解的新HDAC抑制剂.

主要成果:

模拟MD提供关键的非结合性相互作用参数,以评估蛋白质 - 连接体复合物的兼容性.
基于碎片的方法,以MD数据为指导,可以设计潜在的抗癌化合物.
从已知的抑制剂设计的新型抗癌化合物的综述,如拉加二醇,三素A和伏利诺斯塔特.

结论:

MD模拟为开发新型治疗剂提供了强大的直接药物设计策略.
这种方法有助于在进行广泛的实验室合成和测试之前合理设计潜在的候选药物.
该审查旨在鼓励药物化学家在药物开发管道中采用MD模拟,特别是对于像HDACs这样的目标.

关键词:

药物设计药物设计在HDAC的基础上,HDAC是分子动力学模拟模型无约束的能量无约束的能量蛋白质 - 配体复合体. 蛋白质 - 配体复合体.在QSAR中使用QSAR.

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