Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein.

Article Details

Citation

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

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
BromocriptineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
ClotrimazoleP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Inducer
Details
DihydroergotamineP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
ErgometrineP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
ErgotamineP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
KetoconazoleP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
MibefradilP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Details
MiconazoleP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
ReserpineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inhibitor
Inducer
Details
TroleandomycinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
BromocriptineP-glycoprotein 1Ki (nM)3960N/AN/ADetails
BromocriptineP-glycoprotein 1Ki (nM)2810N/AN/ADetails
ClotrimazoleP-glycoprotein 1Ki (nM)44000N/AN/ADetails
ClotrimazoleP-glycoprotein 1Ki (nM)29920N/AN/ADetails
CyclosporineP-glycoprotein 1Ki (nM)1300N/AN/ADetails
CyclosporineP-glycoprotein 1Ki (nM)4660N/AN/ADetails
DihydroergotamineP-glycoprotein 1Ki (nM)>1000000N/AN/ADetails
DihydroergotamineP-glycoprotein 1Ki (nM)120000N/AN/ADetails
ErgometrineP-glycoprotein 1Ki (nM)>100000N/AN/ADetails
ErgometrineP-glycoprotein 1Ki (nM)115500N/AN/ADetails
ErgotamineP-glycoprotein 1Ki (nM)98900N/AN/ADetails
ErgotamineP-glycoprotein 1Ki (nM)14250N/AN/ADetails
ErythromycinP-glycoprotein 1Ki (nM)>1000000N/AN/ADetails
ErythromycinP-glycoprotein 1Ki (nM)37790N/AN/ADetails
FluconazoleP-glycoprotein 1Ki (nM)>1000000N/AN/ADetails
FluconazoleP-glycoprotein 1Ki (nM)>400000N/AN/ADetails
KetoconazoleP-glycoprotein 1Ki (nM)5270N/AN/ADetails
KetoconazoleP-glycoprotein 1Ki (nM)24900N/AN/ADetails
MibefradilP-glycoprotein 1IC 50 (nM)1200N/AN/ADetails
MiconazoleP-glycoprotein 1Ki (nM)55500N/AN/ADetails
MiconazoleP-glycoprotein 1Ki (nM)26360N/AN/ADetails
ReserpineP-glycoprotein 1Ki (nM)970N/AN/ADetails
ReserpineP-glycoprotein 1Ki (nM)12200N/AN/ADetails
TroleandomycinP-glycoprotein 1Ki (nM)87640N/AN/ADetails
TroleandomycinP-glycoprotein 1Ki (nM)483300N/AN/ADetails