Development of hydrophobic interaction field for rational drug design

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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