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针对KEAP1凯尔奇域的基于和小分子的药物发现的结构见解:一篇综述

Suman Sinha¹, Ram Kumar¹, Niraj Kumar Singh¹

¹Institute of Pharmaceutical Research, GLA University, Mathura, Uttar Pradesh, India.

Bioorganic & medicinal chemistry

|July 25, 2025

概括

研究人员分析了112个KEAP1结构,以了解小分子如何抑制KEAP1-Nrf2通路. 像结合这样的关键相互作用稳定了这些抑制剂,帮助开发药物治疗与这种途径相关的疾病.

科学领域:

生物化学生物化学
结构生物学结构生物学
药用化学医学化学

背景情况:

KEAP1-Nrf2通路对于细胞对压力的反应和维持氧化还原平衡至关重要.
这种途径的失调与癌症,神经退行性疾病和糖尿病等严重疾病有关.
针对KEAP1凯尔赫域提供了一个治疗策略来调节Nrf2活动.

研究的目的:

在过去的20年里,编译和分析了112个KEAP1结构与配体共结晶.
为了研究决定向KEAP1-Nrf2相互作用的抑制剂的强度的相互作用.
根据化学结构和生物功效对小分子联体进行分类.

主要方法:

对112个KEAP1蛋白质数据库 (PDB) 记录进行了全面审查.
对联合结晶的和小分子连接体的分析.
小分子根据化学结构的分类 (例如,纳夫他林,异诺林,皮拉).
确定KEAP1凯尔赫域内的关键稳定相互作用.

主要成果:

小分子联体被化学支架分类,包括纳夫他林,异诺林,佐特醇,皮拉和阿扎比环.
稳定KEAP1-连接体复合物的主要相互作用包括结,阴离子-π,π-π堆叠和盐桥.
这些相互作用集中在奥思特里克部位,对于抑制功效至关重要.

结论:

结构洞察力揭示了控制KEAP1-Nrf2通路抑制的关键相互作用.
了解这些相互作用有助于合理设计新的选择性和小分子抑制剂.
这项研究支持开发治疗与KEAP1-Nrf2通路功能障碍相关的疾病的疗法.

关键词:

相互作用相互作用凯尔奇域是一个凯尔奇域.宏分子晶体学宏分子晶体学神经退行性疾病的神经退行性疾病在P1P6子口袋中.酸是一种酸.小分子是小分子.

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