一种酸铁胺类同类物和两个酸盐衍生物的意外相对水溶性
Stefan Boresch1, Martin Leitgeb, Aleksandra Beselman
1Biomolecular Simulation Group, Institut für Biomolekulare Strukturchemie, Universität Wien, Währingerstrasse 17, 1090 Vienna, Austria. stefan@mdy.univie.ac.at
Journal of the American Chemical Society
|March 31, 2005
概括
在药物设计中,用于提高稳定性和结合性的酸类型的酸铁 (pTyr). 化增强了结合,增加了疏水性,同时保持了结合能力,影响了药物的疗效.
科学领域:
- 生物化学 生物化学
- 计算化学计算化学
- 药物发现 药物发现 药物发现
背景情况:
- 氨酸 (pTyr) 对于生物信号和蛋白质相互作用至关重要.
- 由于其增强的稳定性和结合亲和力,对酸盐等pTyr类似物进行药物发现的探索.
- 了解水溶性在结合亲和力中的作用是设计有效抑制剂的关键.
研究的目的:
- 量化水溶性对pTyr类似物结合亲和力的影响.
- 调查pTyr模拟物之间溶解和结合差异的分子基础.
- 为了解选择性化在增强连接体结合功能的作用提供见解.
主要方法:
- 在酸 (PP),酸 (BP) 和二酸 (F(2) BP) 模仿剂上进行了自由能量扰动计算.
- 经验力场参数与CHARMM兼容的经验力场参数得到开发.
- 计算了各种色胺类类似物的溶解自由能量和结合亲和力.
主要成果:
- 酸 (BP) 呈现出最有利的溶解,其次是酸 (PP),而二酸 (F(2) BP是最不有利的溶解.
- 电荷分布,原子大小和局部溶解的差异影响了观察到的溶解顺序.
- 水溶性显著影响pTyr,甲 (Pmp) 和含酸的二甲 (F(2) Pmp的相对结合强度.
结论:
- 选择性化可以通过增加疏水性,同时保持结能力来增强连接体结合亲和力.
- 水溶性的差异是药物设计中pTyr类似物有效性的关键因素.
- 计算方法为信号分子的结合亲和力的分子决定因素提供了宝贵的见解.
相关概念视频
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03:10Precipitation Reactions
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02:30Water: A Bronsted-Lowry Acid and Base
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02:54Ions as Acids and Bases
Salts with Acidic Ions
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03:24Common Ion Effect
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04:01Factors Affecting Solubility
Compared with pure water, the solubility of an ionic compound is less in aqueous solutions containing a common ion (one also produced by dissolution of the ionic compound). This is an example of a phenomenon known as the common ion effect, which is a consequence of the law of mass action that may be explained using Le Chȃtelier’s principle. Consider the dissolution of silver iodide: