Development of hydrophobic interaction field for rational drug design

分配系数logp是定量表达药用/农化药物和环境有毒化学品疏水性的重要参数。本研究项目的目的是通过理论和实验方法了解和预测各种简单有机分子在原子/电子水平上的对数P值。第二个目标是发展由log P分析衍生的“疏水相互作用场”，并将其作为一种基于定量构效关系的新型三维结构应用于合理药物设计领域。研究结果总结如下：(1)我们假设分配过程的熵和焓部分分别近似表示为溶质分子的可达表面积和有机相与水相的拯救能之差。采用ab - ini - More - scrf理论计算了各相的拯救能。我们发现logp值可以用这两项的线性组合来定性地表示，并且溶质的氢键能力决定了分配过程。(2)我们开发了一个三维疏水描述符，该描述符来源于Log P.在几种HIV蛋白酶抑制剂的大量可能的构象与蛋白酶的虚拟对接中，该描述符对于选择它们的实验结合构象具有重要意义。这表明疏水性在药物-受体相互作用中起重要作用。此外，我们计算了药物的pH依赖对数P值，发现该值与药物在乳/血浆相浓度比（MIP）之间有很好的相关性。这一结果提示对数P可以应用于M/P比值等临床数据的分析。(3)我们开发了一种新的基于反馈的流量比率法来测定logp，并将该方法应用于呋喃衍生物的测量。它们的对数P值很难用传统的摇瓶法测量。同时，我们也用这种方法得到了各种含氮芳烃的log P值。这些测量的log P值将成为(1)进一步分析的新的可靠数据集。少

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