使用逆相液态染色学估计分子碎片的疏水程度
Andrea Carotti1, Ina Varfaj1, Ilaria Pruscini1
1Department of Pharmaceutical Sciences, Via Fabretti 48, University of Perugia, Perugia, Italy.
Journal of separation science
|July 13, 2023
概括
一种新的HPLC方法准确地测量了药物发现的分子疏水性. 这种方法克服了小样本尺寸的局限性,并将物理化学评估扩展到具有挑战性的分子碎片.
科学领域:
- 分析化学 分析化学
- 药用化学 医学化学
- 计算化学的计算化学
背景情况:
- 像疏水性这样的物理化学性质对于药物发现至关重要.
- 在药物发现早期阶段,样本的有限可用性对表征提出了挑战.
- 电位计定位对于在特定范围之外确定log D值具有局限性.
研究的目的:
- 开发一种快速的高性能液态染色学 (HPLC) 方法来评估分子疏水性.
- 为了能够准确地对药物相关的分子碎片进行物理化学评估,即使样本数量有限.
- 建立一种可靠的方法来估计超出电位计定位范围的log D值.
主要方法:
- 使用各种参数 (有机修饰剂,静态相,添加剂) 的逆相HPLC (RP-HPLC) 方法的优化.
- 染色学指数的计算,根据皮尔森相关系数 (r) 选择的"φ0指数"与实验LOG D值.
- 在φ0指数和分子描述符 (键捐赠者,凝聚性相互作用指数) 之间的相关性分析.
主要成果:
- 一种优化的RP-HPLC方法在φ0指数和log D值之间实现了强烈的相关性 (r=0.94,p<0.001).
- φ0指数成功估计了四个分子碎片的log D,其中电位计定位失败了.
- 分子描述符,特别是键捐赠者和凝聚性相互作用指数,解释了观察到的φ0值.
结论:
- 开发的快速HPLC方法对于量化药物发现中的分子疏水性是有效的.
- 从HPLC获得的φ0指数为log D确定提供了有价值的替代方案,特别是对于具有挑战性的化合物.
- 这种方法提高了在药物发现管道的早期描述分子碎片的能力.
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