Two- and three-dimensional QSAR of carrier-mediated transport of β-lactam antibiotics in Caco-2 cells
✍ Scribed by Suchada Wanchana; Fumiyoshi Yamashita; Hideto Hara; Shin-Ichi Fujiwara; Miki Akamatsu; Mitsuru Hashida
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 170 KB
- Volume
- 93
- Category
- Article
- ISSN
- 0022-3549
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✦ Synopsis
In this study, we investigated whether such a topological descriptor-based approach is suitable for predicting the carrier-mediated transport of 20 b-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 algorithmcombined 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 b-lactam antibiotics in Caco-2 cells obtained from the literature ranged from À1.15 to 1.09 (nmol/cm 2 /2 h). When preliminary leave-one-out cross-validated partial least squares analyses implemented in the SYBYL/ CoMFA program were conducted, the r pred 2 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 (r pred 2 ¼ 0.923, s ¼ 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.