Because no kinetic principles have been proposed for designing orally effective prodrugs, the author recently reported a kinetic model for membrane transport of prodrugs (Chem-Bio Informatics Journal, 8, 25-32 (2008)), and proposed the kinetic classification and criteria for effective membrane-permeable prodrugs (KCCEMP). The present study addressed more practical conditions, where a prodrug is metabolized/degraded to a drug in the luminal tract after oral administration. Primary factors in orally effective prodrugs are luminal degradation/metabolism and absorption clearance (permeability), which includes the mechanism of membrane transport and metabolism in intestinal cells. The fraction of absorbed prodrug is expressed by the functions of these parameters. Based on the required improvement ratio of the absorption clearance, the kinetic classification and criteria of orally effective prodrugs (KCCOEP) are proposed as a decision tree with conditional equations for guiding kinetic assessment and strategy for the rational development of prodrugs. The assessment of lenampicillin, which was selected as an example of successful prodrugs, according to the procedure indicated a significant impact of luminal degradation/metabolism on the absorbed fraction, and suggests that most ester-type prodrugs on the market degrade in the luminal tract. Thus, a comprehensive study on the fraction of luminal degradation/metabolism and the absorption clearance (permeability) should be conducted to develop orally effective prodrugs, in particular, quantitative assessment of the fraction of contribution (fc,dd) of the drug formed from the prodrug in the luminal tract to the absorption following oral administration of the prodrug is emphasized.

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The n-alkyl sulfates (AS) are a class of anionic surfactants that are widely used in industry and in consumer products. In this study, the effects of AS on yeast growth and genome wide transcriptional profiles were analysed by DNA microarray technology. Induced genes were categorized by localization of gene products and by function according to accepted gene ontologies using the MIPS database. A number of genes whose products localized to the cell wall and peroxisome were significantly induced. Genes involved in energy metabolism (i.e., fatty acid &bete;-oxidation pathway) were also significantly induced. To confirm the role of these functions, the sensitivity of selected single gene deletion strains to sodium dodecyl sulfate (SDS) was tested. Deletion strains of cell wall maintenance genes (ΔGAS1,ΔKRE6, and ΔCHS5) were found to be highly sensitive. Interestingly, mutants deleted for genes in the fatty acid &bete;-oxidation pathway were not found to be sensitive. However, regulating genes in the fatty acid &bete;-oxidation pathway were found to respond to SDS exposure in a dose-dependent manner and to be involved in H2O2 production. Here, we report a functional genomics analysis of genome-wide expression data to screen and evaluate AS toxicity in yeast. While the approach begins with a determination of highly-induced genes, its power lies in then determining the most relevant functions targeted by AS, and then assessing loss of key genes by evaluating AS sensitivity in the corresponding deletion mutants.

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In the field of drug discovery, high-throughput screening (HTS) is widely used to identify new lead compounds. A considerable number of hit compounds, however, will subsequently be found to have low activities when their inhibitory activities are measured more precisely. Such compounds are called false positives. For a more efficient selection of lead compounds, virtual screening methods with QSAR models have been investigated, but no definitive solutions have been found. In this study, we propose an effective method to identify lead compounds. The proposed method is based on rough set theory (RST), which is a mathematical tool for depicting the uncertainty and vagueness of knowledge. The essential parts of RST are the construction of reducts, which are minimal subsets of variables to distinguish samples, and the extraction of rules using their reducts. By applying RST to the QSAR study of monoamine oxidase (MAO) inhibitors, we extracted several rules for identifying lead compounds. First, 3D-structures of MAO inhibitors were generated uniformly by CORINA, and chemical descriptors were calculated by the Volsurf method. Finally, three unique rules were extracted by using RST. It is found that the each rule is chemically reasonable and compatible with previous studies. Furthermore, the predictive power of RST was also proved by comparison with partial least squares (PLS) and decision tree (DT). These results demonstrate the usefulness of our method.

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The coiled coil structure in proteins is characterized by heptad repeats of hydrophobic amino acids, but many breaks of the heptad repeats are observed within coiled coil regions which are the main cause of the errors in the currently used prediction systems for coiled coils. For understanding the characteristics of coiled coils including heptad breaks, the features of coiled coils were studies focusing on three problems: (1) the determination of appropriate register for the breaks in heptad repeat regions, (2) the discriminations of coiled coil regions using physical properties of amino acid segments which have heptad repeats and (3) the elucidation of the structural difference among several types of heptad breaks. Appropriate registers of heptad repeats and breaks were determined by two steps: first, the typical template of heptad repeats was applied to amino acid sequences and then several types of template for heptad breaks were applied to the segments around inconsistent points of the heptad repeat regions, leading to the most appropriate registers. Then, the coiled coil regions were discriminated from other types of regions by the canonical discriminant analysis, using ten parameters (three physicochemical properties and seven number densities of amino acids). The novel coiled coil prediction system SOSUIcoil showed better performances of coiled coil prediction than other prediction systems. Furthermore, the structures of segments around the heptad breaks were analyzed, indicating that some types of heptad breaks tend to form coiled coil structure whereas the other types are at the end of coiled coils.

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