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Molecular Pharmacology

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Research ArticleArticle

In Silico Screening for Inhibitors of P-Glycoprotein That Target the Nucleotide Binding Domains

Frances K. Brewer, Courtney A. Follit, Pia D. Vogel and John G. Wise
Molecular Pharmacology December 2014, 86 (6) 716-726; DOI: https://doi.org/10.1124/mol.114.095414
Frances K. Brewer
Department of Biological Sciences, the Center for Drug Discovery, Design and Delivery, and the Center for Scientific Computing, Southern Methodist University, Dallas, Texas
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Courtney A. Follit
Department of Biological Sciences, the Center for Drug Discovery, Design and Delivery, and the Center for Scientific Computing, Southern Methodist University, Dallas, Texas
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Pia D. Vogel
Department of Biological Sciences, the Center for Drug Discovery, Design and Delivery, and the Center for Scientific Computing, Southern Methodist University, Dallas, Texas
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John G. Wise
Department of Biological Sciences, the Center for Drug Discovery, Design and Delivery, and the Center for Scientific Computing, Southern Methodist University, Dallas, Texas
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Abstract

Multidrug resistances and the failure of chemotherapies are often caused by the expression or overexpression of ATP-binding cassette transporter proteins such as the multidrug resistance protein, P-glycoprotein (P-gp). P-gp is expressed in the plasma membrane of many cell types and protects cells from accumulation of toxins. P-gp uses ATP hydrolysis to catalyze the transport of a broad range of mostly hydrophobic compounds across the plasma membrane and out of the cell. During cancer chemotherapy, the administration of therapeutics often selects for cells which overexpress P-gp, thereby creating populations of cancer cells resistant to a variety of chemically unrelated chemotherapeutics. The present study describes extremely high-throughput, massively parallel in silico ligand docking studies aimed at identifying reversible inhibitors of ATP hydrolysis that target the nucleotide-binding domains of P-gp. We used a structural model of human P-gp that we obtained from molecular dynamics experiments as the protein target for ligand docking. We employed a novel approach of subtractive docking experiments that identified ligands that bound predominantly to the nucleotide-binding domains but not the drug-binding domains of P-gp. Four compounds were found that inhibit ATP hydrolysis by P-gp. Using electron spin resonance spectroscopy, we showed that at least three of these compounds affected nucleotide binding to the transporter. These studies represent a successful proof of principle demonstrating the potential of targeted approaches for identifying specific inhibitors of P-gp.

Footnotes

    • Received August 12, 2014.
    • Accepted September 29, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant 1R15-GM094771-01A1] (to P.D.V. and J.G.W.), and the Southern Methodist University (SMU) Research Council, the SMU Dedman College Dean’s Research Council, the Dedman College Center for Drug Discovery, Design and Delivery, and the Communities Foundations of Texas, Dallas. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

  • dx.doi.org/10.1124/mol.114.095414.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (6)
Molecular Pharmacology
Vol. 86, Issue 6
1 Dec 2014
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Research ArticleArticle

Identification of Targeted P-Glycoprotein Inhibitors

Frances K. Brewer, Courtney A. Follit, Pia D. Vogel and John G. Wise
Molecular Pharmacology December 1, 2014, 86 (6) 716-726; DOI: https://doi.org/10.1124/mol.114.095414

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Research ArticleArticle

Identification of Targeted P-Glycoprotein Inhibitors

Frances K. Brewer, Courtney A. Follit, Pia D. Vogel and John G. Wise
Molecular Pharmacology December 1, 2014, 86 (6) 716-726; DOI: https://doi.org/10.1124/mol.114.095414
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