Two‐ and three‐dimensional QSAR of carrier‐mediated transport of β‐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 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/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 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  = 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

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