title: [High throughput screening of pharmacokinetics and metabolism in drug discovery (III)--investigation on in- silico model for membrane permeability and CYP1A2 inhibition].
abstract: Pharmacokinetic and metabolic screening plays an important role in the optimization of a lead compound in drug discovery. Since those screening methods are time-consuming and labor intensive, in silico models would be effective to select compounds and guide derivatization prior to the screening. We investigated in silico models for permeability in Caco-2 cells, brain distribution and cytochrome P450 (CYP) inhibition using molecular weight, lipophilicity (clog D(7.4)), polar surface area (PSA), and number of rotatable bonds (RB). A variety of test compounds was selected from different Caco-2 assay projects. The permeability determined exhibited a good correlation with a combination of PSA and clog D(7.4) rather than with PSA alone. In the brain distribution, PSA, in addition to lipophilicity, was one of the determinant parameters, and compounds were significantly distributed to the brain in rats with the decrease in the PSA value. When this approach was adapted to CYP1A2 inhibition in the fluorometric assay, the inhibitory potential for two plane core structures was successfully predicted by utilizing number of RB, PSA, and clog D(7.4). In particular, an increase in the number of RB weakened the inhibitory potential due to a loss of the plane structures. These results suggest that the PSA and RB are key parameters to design chemical structures in terms of the improvement of both membrane permeability in the brain and gastrointestine and CYP1A2 inhibition, respectively.
authors.affiliation: Department of Research Pharmacokinetics, Research Center Kyoto, Bayer Yakuhin, Ltd., Kyoto 619-0216, Japan. hiroshi.komura.hk@bayer.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komura
authors.forename: Yukie
authors.initials: Y
authors.lastname: Shigemoto
authors.forename: Iichiro
authors.initials: I
authors.lastname: Kawahara
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Rieko
authors.initials: R
authors.lastname: Ano
authors.forename: Yoko
authors.initials: Y
authors.lastname: Murayama
authors.forename: Toshiya
authors.initials: T
authors.lastname: Moriwaki
authors.forename: Nagahiro H
authors.initials: NH
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D008297:Male; D010599:Pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D001798:Blood Proteins; D065609:Cytochrome P-450 CYP1A2 Inhibitors