Functional assay and structure-activity relationships of new third-generation P-glycoprotein inhibitors.

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Muller H, Pajeva IK, Globisch C, Wiese M

Functional assay and structure-activity relationships of new third-generation P-glycoprotein inhibitors.

Bioorg Med Chem. 2008 Mar 1;16(5):2448-62. Epub 2007 Nov 28.

PubMed ID
18083034 [ View in PubMed
]
Abstract

Twenty-eight compounds, including 24 structurally related derivatives of tariquidar synthesized in our laboratory, and four XR compounds, reported by Xenova group Ltd, were investigated by the Hoechst 33342 and Calcein AM functional assays for estimation of their inhibitory effects on the transport activity of P-glycoprotein (P-gp). A high correlation between the effects obtained in both assays was observed at the substrate concentrations used. The analyses of kinetics data from experiments at different substrate concentrations revealed non-competitive inhibition in the Calcein AM assay and competitive inhibition in the Hoechst 33342 assay. The 3D structures of the compounds were further aligned on Hoechst 33342 using flexible and pharmacophore alignments. The results suggested that inhibitors could interact with the H-binding site of P-gp and this could potentially be achieved by different ways of binding. The best 3D-QSAR models, generated by CoMFA and CoMSIA, yielded an internal predictive squared correlation coefficient higher than 0.8 and included electrostatic, steric, hydrogen bond acceptor, and hydrophobic fields. Validation of the models on an external test set of 30 XR compounds gave predictive squared correlation coefficients of up to 0.66. An excellent correspondence between the experimental and modeled activities of the test compounds was observed. The models can be used for prediction and rational design of new P-gp inhibitors.

DrugBank Data that Cites this Article

Drugs
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CyclosporineP-glycoprotein 1IC 50 (nM)440N/AN/ADetails
CyclosporineP-glycoprotein 1IC 50 (nM)1412.54N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)4571N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)6607N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)5800N/AN/ADetails
VerapamilP-glycoprotein 1IC 50 (nM)5754N/AN/ADetails