Application of Three-Dimensional Quantitative Structure-Activity Relationships of P-Glycoprotein Inhibitors and Substrates

Abstract

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.

Determination and modelling of stereoselective interactions of ligands with drug transporters: A key dimension in the understanding of drug disposition

“…The necessity for the development of multiple models reflects the fact that Pgp contains multiple binding sites as was observed by the authors (Ekins et al 2002b) and that these sites are affected by the conformational mobility of the protein (cf. Sonveaux et al 1996; Lu et al 2001a).…”

“…However, the stereochemical aspects of substrate–transporter and inhibitor–transporter interactions were not addressed in these papers. Indeed, chiral compounds were used in the development of the Pgp models (Ekins et al 2002a, 2002b) and hOCT1 (Bednarczyk et al 2003) but the chirality of the compounds was ignored and/or racemic mixtures were used instead of the single enantiomer. The result is that the models were unable to provide an accurate three-dimensional view of the transporter and the binding interactions.…”

“…Five three-dimensional QSAR models describing the binding of various substrates to Pgp have been recently described (Ekins et al 2002a, 2002b). The necessity for the development of multiple models reflects the fact that Pgp contains multiple binding sites as was observed by the authors (Ekins et al 2002b) and that these sites are affected by the conformational mobility of the protein (cf.…”

“…These models were constructed using IC 50 and K i data obtained for digoxin transport, VBL and calcein accumulation and VBL binding (Ekins et al 2002a) and the inhibition of VER binding (Ekins et al 2002b). In both of these studies chiral molecules were used in the training and test sets, but the stereochemistry was not considered.…”

“…In this study, the only enantioselective interaction was observed with carvedilol where the IC 50 value for R -carvedilol was significantly lower than the value for S -carvedilol (Table I). Enantioselective interactions with Pgp have been recently reported (Table I) (Ekins et al 2002a, 2002b). In these studies, significant enantioselectivities were observed for two of the compounds, α=2.26 and 4.92.…”