Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein.
Article Details
-
Citation
Copy to clipboard -
Ekins S, Kim RB, Leake BF, Dantzig AH, Schuetz EG, Lan LB, Yasuda K, Shepard RL, Winter MA, Schuetz JD, Wikel JH, Wrighton SA
Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein.
Mol Pharmacol. 2002 May;61(5):964-73.
- PubMed ID
-
11961113 [View in PubMed]
- Abstract
-
P-glycoprotein (P-gp) is an efflux transporter involved in limiting the oral bioavailability and tissue penetration of a variety of structurally divergent molecules. A better understanding of the structural requirements of modulators of P-gp function will aid in the design of therapeutic agents. Toward this goal, three-dimensional quantitative structure-activity relationship (3D-QSAR) models were generated using in vitro data associated with inhibition of P-gp function. Several approaches were undertaken with multiple iterations, yielding Catalyst 3D-QSAR models being able to qualitatively rank-order and predict IC(50) values for P-gp inhibitors excluded from the model in question. The success of these validations suggests that a P-gp pharmacophore for 27 inhibitors of digoxin transport in Caco-2 cells consisted of four hydrophobes and one hydrogen bond acceptor. A second pharmacophore generated with 21 inhibitors of vinblastine binding to plasma membrane vesicles derived from CEM/VLB(100) cells contained three ring aromatic features and one hydrophobic feature. A third pharmacophore generated with 17 inhibitors of vinblastine accumulation in P-gp expressing LLC-PK1 cells contained four hydrophobes and one hydrogen bond acceptor. A final pharmacophore was generated for inhibition of calcein accumulation in P-gp expressing LLC-PK1 cells and found to contain two hydrophobes, a ring aromatic feature, and a hydrogen bond donor. The similarity of features for the pharmacophores of P-gp inhibitors of digoxin transport and vinblastine binding suggest some commonality in their binding sites. Utilization of such models may prove to be of value for prediction of molecules that may modulate one or more P-gp binding sites.
DrugBank Data that Cites this Article
- 药物转运蛋白
-
Drug Transporter Kind Organism Pharmacological Action Actions Bromocriptine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Clotrimazole P-glycoprotein 1 Protein Humans UnknownInhibitorInducerDetails Dihydroergotamine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Ergometrine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Ergotamine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Ketoconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Mibefradil P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorDetails Miconazole P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Reserpine P-glycoprotein 1 Protein Humans UnknownSubstrateInhibitorInducerDetails Troleandomycin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails - Binding Properties