Loading…
Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates
Using in vitro data, we previously built Catalyst 3-dimensional quantitative structure activity relationship (3D-QSAR) models that qualitatively rank and predict IC 50 values for P-glycoprotein (P-gp) inhibitors. These models were derived and tested with data for inhibition of digoxin transport, cal...
Saved in:
Published in: | Molecular pharmacology 2002-05, Vol.61 (5), p.974-981 |
---|---|
Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Using in vitro data, we previously built Catalyst 3-dimensional quantitative structure activity relationship (3D-QSAR) models
that qualitatively rank and predict IC 50 values for P-glycoprotein (P-gp) inhibitors. These models were derived and tested with data for inhibition of digoxin transport,
calcein accumulation, vinblastine accumulation, and vinblastine binding. In the present study, 16 inhibitors of verapamil
binding to P-gp were predicted using these models. These inhibition results were then used to generate a new pharmacophore
that consisted of one hydrogen bond acceptor, one ring aromatic feature, and two hydrophobes. This model predicted the rank
order of the four data sets described previously and correctly ranked the inhibitory potency of a further four verapamil metabolites
identified in the literature. The degree of similarity in rank ordering prediction by these inhibitor pharmacophore models
generated to date confirms a likely overlap in the sites to which the three P-gp substrates used in these studies (verapamil,
vinblastine, and digoxin) bind. Alignment of the three substrate probes indicated that they are likely to bind the same or
overlapping sites within P-gp. Important features on these substrates include multiple hydrophobic and hydrogen bond acceptor
features, which are widely dispersed and in agreement among most of the five inhibitor pharmacophores we have described so
far. These 3D-QSAR models will be useful for future prediction of likely substrates and inhibitors of P-gp. |
---|---|
ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.61.5.974 |