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Development of hydrophobic interaction field for rational drug design

合理药物设计疏水相互作用场的发展

基本信息

批准号：
14572094
负责人：
CHUMAN Hiroshi
金额：
$ 2.24万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14572094/
关键词：
partition coefficient Log P hydrophobicity Quantitative Structure-Activity Relationship ab initio MO continuous flow analysis rational drug design clinical data analysis ab initio MO log-P n-Octanol QSAR 水素結合疎水相互作用溶媒接触表面積溶

项目摘要

The partition coefficient log P is known to be an important Parameter that expresses the hydrophobicity of medicinal/agrochemical drugs and environmental toxic chemicals quantitatively. The aim of this research project is to understand and to predict the log P values of various simple organic molecules at their atomic/electronic level by both theoretical and experimental approaches. The second aim is to develop the "hydrophobic interaction field" derived from the analyses of log P, and to apply it in the field of rational drug design as a novel three-dimensional structure based Quantitative Structure-Activity Relationship.The research results are summarized briefly as follows :(1)We assumed that, the entropic and enthalpic parts of the partitioning process are approximately expressed by the accessible surface area of a solute molecule and the difference of the salvation energies between organic and water phases, respectively. The salvation energy in each phase was obtained by an ab ini … More tio-SCRF theory. We found that the log P value is expressible qualitatively by a liner combination of these two terms and that the hydrogen bonding ability of a solute governs the partitioning process.(2)We developed a three-dimensional hydrophobic descriptor, which was derived from Log P. In the virtual docking of a huge number of possible conformers of several HIV protease inhibitors with the protease, this descriptor was significant for selecting their experimentally bound conformation. This result suggests that the hydrophobicity plays an important role in the drug-receptor interaction. Furthermore, we calculated the pH dependent log P value of medicinal drugs and found a nice correlation between this value and the concentration ratio of drugs in milk/plasma phases (MIP). This result suggests log P will be applicable for analyses of clinical data such as the M/P ratio.(3)We developed a novel feedback-based flow ratiometry for the determination of log P. We applied this method to measure furan derivatives. Their log P values are difficult to be measured by a conventional shake-flask method. Also, we obtained the log P values of various nitrogen containing aromatics by this method. These measured log P values will be a new reliable data set for further analyses for (1). Less

已知分配系数log P是定量表示医药/农用化学药物和环境有毒化学品的疏水性的重要参数。该研究项目的目的是通过理论和实验方法来理解和预测各种简单有机分子在原子/电子水平上的log P值。第二个目标是发展由log P分析得到的“疏水相互作用场”，并将其作为一种新的基于三维结构的定量构效关系应用于合理药物设计领域。（1）我们假定分配过程的熵和熵部分近似地用溶质分子的可及表面积和有机相与水相的拯救能之差来表示，分别用从头算方法求出了各相的拯救能 ...更多信息 tio-SCRF理论我们发现，对数P值是定性表示的线性组合，这两个方面和溶质的氢键结合能力支配的分区过程。(2)We开发了一个三维疏水描述符，这是来自Log P。在虚拟对接的大量可能的构象的几个HIV蛋白酶抑制剂与蛋白酶，这个描述符是重要的选择他们的实验结合构象。这一结果表明疏水性在药物-受体相互作用中起重要作用。此外，我们还计算了药物的pH依赖性log P值，并发现该值与药物在乳/血浆相（MIP）中的浓度比之间存在良好的相关性。该结果表明log P将适用于临床数据分析，如M/P比值。(3)We开发了一种新的反馈为基础的流量比测定log P。我们应用这种方法来测量呋喃衍生物。它们的log P值很难用常规的摇瓶法测定。同时，我们用这种方法得到了各种含氮芳烃的logP值。这些测得的log P值将是进一步分析（1）的新的可靠数据集。少