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

Publication type:
Journal article
Metadata:
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Massimo Valoti
  • Maria Frosini
  • Giampietro Sgaragli
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000371952600005&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1016/j.bcp.2016.01.014
eISSN
1873-2968
Externe Identifier
  • Clarivate Analytics Document Solution ID: DG3EP
  • PubMed Identifier: 26807479
ISSN
0006-2952
Zeitschrift
BIOCHEMICAL PHARMACOLOGY
Schlüsselwörter
  • Cancer drug resistance
  • Molecular docking
  • N,N-Bis(cyclohexanolamine)aryl ester
  • P-glycoprotein
Paginierung
42 - 51
Datum der Veröffentlichung
2016
Status
Published
Titel
Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses
Sub types
  • Article
Ausgabe der Zeitschrift
104

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Massimo Valoti
  • Maria Frosini
  • Giampietro Sgaragli
  • Thomas Efferth
DOI
10.1016/j.bcp.2016.01.014
ISSN
0006-2952
Zeitschrift
Biochemical Pharmacology
Sprache
en
Paginierung
42 - 51
Datum der Veröffentlichung
2016
Status
Published
Herausgeber
Elsevier BV
Herausgeber URL
http://dx.doi.org/10.1016/j.bcp.2016.01.014
Datum der Datenerfassung
2018
Titel
Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses
Ausgabe der Zeitschrift
104

Data source: Crossref

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 either 2c or EPI significantly reduced LBE of both EPI and R123, and that of both (3)H-2EPI and (14)C-2EPI, respectively. Since the clusters of DBD amino acid residues interacting with EPI were different, if EPI docked alone or after pre-docking of EPI or 2c, the existence of alternative secondary binding site for EPI on P-gp is credible. In conclusion, 2c may allocate the drug-binding pocket and reduce strong binding of EPI and R123 in agreement with P-gp inhibition experiments, where 2c reduced efflux of EPI and R123.
Addresses
  • Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Massimo Valoti
  • Maria Frosini
  • Giampietro Sgaragli
  • Thomas Efferth
  • Thomas Efferth
DOI
10.1016/j.bcp.2016.01.014
eISSN
1873-2968
Externe Identifier
  • PubMed Identifier: 26807479
Funding acknowledgements
  • Fondazione Monte dei Paschi di Siena:
  • Istituto Toscano Tumori:
  • Johannes Gutenberg-Universität Mainz:
Open access
false
ISSN
0006-2952
Zeitschrift
Biochemical pharmacology
Schlüsselwörter
  • Cell Line, Tumor
  • Animals
  • Mice
  • Cyclohexanols
  • Esters
  • Rhodamine 123
  • Epirubicin
  • Cell Culture Techniques
  • Transfection
  • Binding Sites
  • Molecular Structure
  • Protein Binding
  • Substrate Specificity
  • Protein Transport
  • Molecular Docking Simulation
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
Sprache
eng
Medium
Print-Electronic
Online publication date
2016
Paginierung
42 - 51
Datum der Veröffentlichung
2016
Status
Published
Datum der Datenerfassung
2016
Titel
Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses.
Sub types
  • Research Support, Non-U.S. Gov't
  • Journal Article
Ausgabe der Zeitschrift
104

Data source: Europe PubMed Central

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 either 2c or EPI significantly reduced LBE of both EPI and R123, and that of both (3)H-2EPI and (14)C-2EPI, respectively. Since the clusters of DBD amino acid residues interacting with EPI were different, if EPI docked alone or after pre-docking of EPI or 2c, the existence of alternative secondary binding site for EPI on P-gp is credible. In conclusion, 2c may allocate the drug-binding pocket and reduce strong binding of EPI and R123 in agreement with P-gp inhibition experiments, where 2c reduced efflux of EPI and R123.
Date of acceptance
2016
Autoren
  • Onat Kadioglu
  • Mohamed EM Saeed
  • Massimo Valoti
  • Maria Frosini
  • Giampietro Sgaragli
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26807479
DOI
10.1016/j.bcp.2016.01.014
eISSN
1873-2968
Zeitschrift
Biochem Pharmacol
Schlüsselwörter
  • Cancer drug resistance
  • Molecular docking
  • N,N-Bis(cyclohexanolamine)aryl ester
  • P-glycoprotein
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Animals
  • Binding Sites
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cyclohexanols
  • Epirubicin
  • Esters
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Transport
  • Rhodamine 123
  • Substrate Specificity
  • Transfection
Sprache
eng
Country
England
Paginierung
42 - 51
PII
S0006-2952(16)00038-1
Datum der Veröffentlichung
2016
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2016
Titel
Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
104

Data source: PubMed

Beziehungen:
Property of

Tools