• Caco-2 cells;
  • membrane transport/transporters;
  • computational ADME;
  • QSAR;
  • structure-transport relationship;
  • partial least squares


In this study, we investigated whether such a topological descriptor-based approach is suitable for predicting the carrier-mediated transport of 20 β-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 β-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 rmath image 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 (rmath image = 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. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:3057–3065, 2004