Abstract
Purpose. To statistically model the permeability across Caco-2 cell monolayers using theoretically computed molecular descriptors and multivariate statistics.
Methods. Seventeen structurally diverse compounds were investigated. The program MolSurf was used to compute theoretical molecular descriptors related to physico-chemical properties such as lipophilicity, polarity, polarizability and hydrogen bonding. The multivariate Partial Least Squares Projections to Latent Structures (PLS) method was used to delineate the relationship between the permeability across Caco-2 cell monolayers and the theoretically computed molecular descriptors.
Results. Excellent statistical models were derived. Properties associated with hydrogen bonding had the largest impact on diffusion through the monolayers and should be kept at a minimum to promote high permeability. High lipophilicity and the presence of surface electrons, i.e. valence electrons, which are not tightly bonded to the molecule, were also found to have a favorable influence to achieve high permeability.
Conclusions. The results indicate that theoretically computed molecular MolSurf descriptors in conjunction with multivariate statistics of PLS type can be used to successfully model permeability across Caco-2 cell monolayers and, thus, differentiate drugs with poor permeability from those with acceptable permeability at an early stage of the pre-clinical drug discovery process.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
REFERENCES
Y. C. Martin. J. Med. Chem. 24:229–237 (1981).
W. D. Stein. The molecular basis of diffusion across membranes. In The Movement of Molecules Across Cell Membranes, Academic Press, New York, 1967, pp. 65–125.
P. Artursson and J. Karlsson. Biochem. Biophys. Res. Commun. 175:880–885 (1991).
L. Amidon, P. J. Sinko, and D. Fleisher. Pharm. Res. 5:651–654 (1988).
H. van de Waterbeemd and M. Kansy. Chimia 46:299–303 (1992).
H. van de Waterbeemd, G. Camenisch, G. Folkers, and O. A. Raevsky. Quant. Struct.-Act. Relat. 15:480–490 (1996).
K. Palm, K. Luthman, A-L. Ungell, G. Strandlund, and P. Artursson. J. Pharm. Sci., 85:32–39 (1996).
MolSurf version 2.0, Qemist AB, Hertig Carls allé 29, S-691 41 Karlskoga, Sweden, e-mail: par.sjoberg@mbox309.swipnet.se.
S. Wold, E. Johansson, and M. Cocchi. PLS-Partial least-squares projections to latent structures. In H. Kubinyi (ed.), 3D QSAR in Drug Design, ESCOM, Leiden, 1993, pp. 523–550.
Macromodel version 5.5, Dept. Chem., Columbia Univ., New York, NY 10027, USA.
Spartan version 4.1, Wavefunction, Inc., 18401 Von Karman Ave., #370, Irvine, CA 92715, USA.
The MolSurf program presently requires an ab initio wavefunction due to the program's current parametrization and underlying methodology. Work is currently under way that will enable the use of semi-empirical AM1 calculations throughout the quantum mechanical parts of the computational protocol.
E. Marengo and R. Todeschini. Chem. Intel. Lab. Systems 16:37–44 (1992).
J. E. Jackson. A Users Guide to Principal Components, Wiley & Sons, New York, 1991.
I. T. Jolliffe. Principal Component Analysis, Springer Verlag, New York, 1986.
E. R. Malinowski. Factor Analysis in Chemistry, 2nd ed., Wiley & Sons, New York, 1991.
S. Wold. Technometrics 20:379–405 (1979).
U. Norinder, unpublished results.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Norinder, U., Österberg, T. & Artursson, P. Theoretical Calculation and Prediction of Caco-2 Cell Permeability Using MolSurf Parametrization and PLS Statistics. Pharm Res 14, 1786–1791 (1997). https://doi.org/10.1023/A:1012196216736
Issue Date:
DOI: https://doi.org/10.1023/A:1012196216736