Chemical modification of an active drug with promoiety to a prodrug ("prodrugging") is a way to improve the pharmacokinetic characteristics of an active drug in the body; however, no kinetic principles have been proposed to design orally effective prodrugs to overcome biological membrane barriers. Therefore, based on a previously reported kinetic model of drug absorption [Mizuma et al., J Pharm. Sci. 85, 854 (1996)], conditional equations for the kinetic strategy of prodrugging were derived. Conditional equations contain terms of uptake (influx) and efflux transport of the prodrug and drug, and the metabolism of the prodrug to drug. Thereby, kinetic classification and criteria for effective membrane-permeable prodrugs are shown as a decision tree with conditional equations. The first point in the kinetic classification and criteria is the uptake process; second, the efflux process is vetted; finally, the metabolic process is elucidated. In some cases, metabolism is not a factor in the better absorption of prodrugs than active drugs. Experiments corresponding to particular processes were proposed, and are applicable to the design of prodrugs not only for intestinal absorption, but also for biological membrane permeation.

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We studied hydration of four types of small nonpeptidic molecule, flavonoid, by molecular dynamics simulations at 300 K with focusing on three physical quantities: solvent density, solvent site-dipole field, and solvent diffusion. The solvent site-dipole field is a quantity recently introduced by us to study directional ordering of water molecules around solute. The spatial patterns of these quantities showed strong site-dependency around the flavonoids. Common to the four flavonoids, high solvent-density sites around hydrophilic solute atoms were characterized by strong directional ordering of water molecule and by depressed solvent diffusive motions. Contrarily, high solvent-density sites around hydrophobic solute surface were characterized by weak directional ordering. The solvent site-dipole field showed specific ordering patterns of water molecules not only in the first solvent layer but also in the second solvent layer. The spatial patterns of the three quantities were conservative among the four flavonoids whether the intra-flavonoid flexibility was large or not. Thus, an adiabatic approximation, which has been assumed in various theoretical hydration studies, was satisfied well. The hydration at a site in the vicinity of solute was determined mainly by the physico-chemical property of the solute atom group nearest to the solvent site, which supports a phenomenological theorem that the solvent accessible surface area of a solute is proportional to the solvation free energy.

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G-protein coupled receptors (GPCRs) bind with G-proteins upon activation by ligands. Understanding the mechanisms of specific binding between GPCRs and G-proteins is one of the most important issues in bioinformatics research. In this study, the physical properties of various regions were analyzed in order to classify GPCRs by G-protein family and to better understand binding specificity. We focused on cytoplasmic loops (IL1, IL2 and N/C-terminus of IL3), extracellular loops (NTL, EL1 and N/C-terminus of EL2) and cytoplasmic termini of transmembrane helices, except for helices that connect to C-terminus loops. The distribution of hydrophobicity, charge density, lysine and arginine densities, and loop length enabled discrimination of GPCRs with more than 90% accuracy.

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