title: Two- and three-dimensional QSAR of carrier-mediated transport of beta-lactam antibiotics in Caco-2 cells.
abstract: In this study, we investigated whether such a topological descriptor-based approach is suitable for predicting the carrier-mediated transport of 20 beta-lactam antibiotics that are substrates of peptide transporters. To select the molecular descriptors that can effectively predict a targeted property in QSAR analysis, the genetic algorithm-combined partial least squares approach was used. The feasibility of the two-dimensional (2D)-QSAR approach was compared with that of comparative molecular field analysis (CoMFA). The logarithm of the uptake values of 20 beta-lactam antibiotics in Caco-2 cells obtained from the literature ranged from -1.15 to 1.09 (nmol/cm2/2 h). When preliminary leave-one-out cross-validated partial least squares analyses implemented in the SYBYL/CoMFA program were conducted, the r2pred was 0.759 and the standard error of prediction (s) was 0.373. However, the 2D-QSAR approach based on Molconn-Z descriptors gave a better predictability (r2pred = 0.923, s = 0.211), where 14 descriptors were selected and the optimal number of principal components was 4. Considering that the 2D-topological descriptors are less computationally intensive and practically completely automated, the simple 2D-QSAR model is also of great importance in drug discovery settings.
authors.affiliation: Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
authors.forename: Suchada
authors.initials: S
authors.lastname: Wanchana
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Yamashita
authors.forename: Hideto
authors.initials: H
authors.lastname: Hara
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Hashida
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001692:Biological Transport / Q000502:physiology; D018938:Caco-2 Cells; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D047090:beta-Lactams / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004337:Drug Carriers; D047090:beta-Lactams