Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses

Biochemical Pharmacology
Onat KadiogluThomas Efferth

Abstract

Rhodamine 123 (R123) transport substrate sensitizes P-glycoprotein (P-gp) to inhibition by compound 2c (cis-cis) N,N-bis(cyclohexanolamine)aryl ester isomer in a concentration-dependent manner in human MDR1-gene transfected mouse T-lymphoma L5178 cells as shown previously. By contrast, epirubicin (EPI) concentration changes left unaltered 2c IC50 values of EPI efflux. To clarify this discrepancy, defined molecular docking (DMD) analyses of 12 N,N-bis(cyclohexanolamine)aryl esters, the highly flexible aryl ester analog 4, and several P-gp substrate/non-substrate inhibitors were performed on human P-gp drug- or nucleotide-binding domains (DBD or NBD). DMD measurements yielded lowest binding energy (LBE, kcal/mol) values (mean ± SD) ranging from -11.8 ± 0.54 (valspodar) to -3.98 ± 0.01 (4). Lys234, Ser952 and Tyr953 residues formed H-bonds with most of the compounds. Only 2c docked also at ATP binding site (LBE value of -6.9 ± 0.30 kcal/mol). Inhibition of P-gp-mediated R123 efflux by 12 N,N-bis(cyclohexanolamine)aryl esters and 4 significantly correlated with LBE values. DMD analysis of EPI, (3)H-1EPI, (3)H-2EPI, (14)C-1EPI, (14)C-2EPI, R123 and 2c before and after previous docking of each of them indicated that pre-docking of ei...Continue Reading

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Citations

Apr 10, 2016·Basic & Clinical Pharmacology & Toxicology·Yuanjin ZhangXin Wang
Mar 25, 2017·Expert Opinion on Therapeutic Targets·Piyush BugdeYan Li
Jun 28, 2017·International Journal of Molecular Sciences·Qiu-Li HouYong-Qiang Zhang
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Feb 22, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Janine NaßThomas Efferth
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Jun 11, 2021·Phytomedicine : International Journal of Phytotherapy and Phytopharmacology·Janine NaßThomas Efferth
Dec 31, 2020·Journal of Chemical Information and Modeling·Rong YangRuizhi Zhao

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