The structures of dioxins were optimized by the ab initio molecular orbital method at the HF/6-31G* level with the Gaussian 98 program package, and then electrostatic potentials were mapped out to explore the pharmacophore image of the receptor complementary to that. The maps were additive on the constitutional atoms, showing similarly the negative values around the oxygen and chlorine atoms and the positive values around the carbon and hydrogen atoms; and with the similarity of the molecular shapes, the applicability of the Comparative Molecular Field Analysis (CoMFA) was anticipated. Total 18 compounds, to which the toxic equivalency factors (WHO-TEF) are given, were used for CoMFA. These compounds consist of three congeners: polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and coplanar poly-chlorinated biphenyls (Coplanar PCBs). CoMFA was executed by using the receptor binding avidities (EC₅₀) as the activity. The receptor was rat hepatic cytosol aryl hydrocarbon receptor (AhR). The structures were superimposed by fitting pairs of atoms so as to minimize RMS of the distances. As the template molecule 1, 2, 3, 7, 8-PeCDD was selected. PCDFs were superimposed to PCDDs in planar position, but twisted PCBs went through from one side of PCDD to the other side. Electrostatic potential derived charges of CHelpG by ab initio HF/6-31G* calculations were given to the structures. Partial least squares gave a cross-validated correlation coefficient q² = 0.955 at the number of components 3. From the correlation, extrapolation to the higher value of bromine derivatives as 2, 3, 7, 8-TBrDD and interpolation to the lower value as 1, 3, 7, 8-TCDD were done.

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In this study we develop a new phylogenetic method to describe within-host (patient) viral evolution. Our method accommodates ordinary phylogenetic tree with viral evolution. Viral genomic data often arise from longitudinal sampling and at each observation time we have many types of viral variants. Our method establishes the phylogenetic relation between these viral variants observed at consecutive time points. Our method also can incorporate both neutral evolution and Darwinian selective evolution. In several viral genomic sites, the Darwinian evolutions are seen, so that the phylogenetic method for the viral evolution should deal with both neutral and selective modes of evolution. We apply Yang's codon-based method to specify when and how neutral and adaptive modes of evolution take place in the course of viral evolution. In our previous study, we proposed the preliminary formulation of our longitudinal phylogenetic tree method, based on the maximum likelihood method. But calculation of likelihood takes much time and number of possible tree topologies increase exponentially according to the increase of number of variants. In this study, we propose another new algorithm, distance-based sequential-linking algorithm using neighbor-joining (NJ) method. We applied this new algorithm to a data of the V3 region of the HIV-1 envelope genes sequenced at different years after the infection of a single patient. The results suggest that this algorithm successfully reconstruct a longitudinal phylogenetic tree that describes the within-host viral evolution.

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To elucidate the correlation between the physicochemical properties and biological activity of sulfonium compound, the kinetics of H-D exchange and methyl transfer reactions were investigated as its remarkable properties. There was a good correlation between acute toxicity (LD₅₀) and rate constants of H-D exchange or methyl transfer reactions. The control of toxicity is very important in the development of a new drug. The high reactivity of methyl group was not desirable in acute toxicity, therefore, sulfonium p-toluenesulfonates that do not contain unsaturated carbon as a substituent of sulfur were desirable for reducing toxicity. Furthermore it was revealed that OH and COOH groups reduced acute toxicity substantially. The information on toxicity reduction was used in the design of Suplatast Tosilate

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Some pyridyl-pyrrole compounds were found to have inhibitory activities against p38 MAP kinase. Their activity was much more potent than that of SB203580 that has a similar overall structure but with a different core group, i.e., an imidazole ring. The complex structure modeling was therefore carried out in an attempt to obtain insights into the interactions of the kinase with the pyridyl-pyrrole compounds and SB203580. The resultant complex models revealed that the imidazole and the pyrrole compounds had similar binding modes and that the representative interactions between the enzyme and the ligand moiety (pyridyl or phenyl) were common. For the sulfoxy moiety including the aliphatic tethers attached to a terminal functional group, the amino acid residues interacting with the moiety were elucidated. Lastly, the affinities of the inhibitors were estimated by calculating the score values with the Ludi program and a good correlation between the p38 MAP kinase inhibitory activities and the score values was found.

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