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三氨酸宏循环库:合成,logD预测,以及一种令人惊的疏水性,膜透性二胺

Gretel A Stokes¹, Casey J Patterson-Gardner¹, Alexander M Engstrom²

¹Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76109, United States.

ACS medicinal chemistry letters

|June 18, 2025

概括

使用添加算法预测分子脂友性 (logP) 需要纠正,因为它们低估了疏水性. 优化合成和pH依赖性研究揭示了分子内键影响宏循环行为.

科学领域:

药用化学医学化学
计算化学计算化学
合成化学合成化学

背景情况:

准确预测脂性对药物发现和开发至关重要.
添加算法被广泛用于预测物理化学性质,如脂性.
由于其复杂的结构,宏循环在预测它们的行为方面存在独特的挑战.

研究的目的:

评估使用添加算法预测三氨酸宏循环的脂友性策略.
为图书馆生成宏循环开发优化的合成路径.
为了研究pH对宏循环疏水性和膜透性的影响.

主要方法:

通过两条不同的路线合成三氨酸宏循环库.
在pH10下通过逆相HPLC测量八醇-水分区系数 (logP).
实验logP值与从加法算法中计算的值 (AlogP) 的比较.
并行人工膜透性测试 (PAMPA) 研究,以评估膜过渡.
结构分析和计算建模以解释观察到的疏水性.

主要成果:

在应用修正因子后,在实验和计算的脂友性值之间观察到线性相关性.
添加算法,没有纠正,低估了100倍的疏水性.
两个宏循环在高pH值时表现出异常的疏水性,这是PAMPA研究证实的.
含有两个主要氨基的同型二元体比含有一个氨基和一个水组的异型二元体更具有疏水性.
氨基酸之间的分子内键被确定为异常行为的原因.

结论:

添加算法可以通过简单的校正因子准确预测宏循环脂友性.
溶液相合成是生成宏循环库的可行策略.
分子内键显著影响了三氨酸宏循环的pH依赖的脂友性和膜透性.

关键词:

潘帕帕是一个庞巴巴.计算计算的计算方式经验算法经验算法经验算法疏水性是指对水的疏水性.在分子内,有键.图书馆图书馆图书馆是一个三亚的三亚是一种

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