In silico study on the interaction between p-glycoprotein and its inhibitors at the drug binding pocket

Namseok Kim, Jae Min Shin, Kyoung Tai No

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

P-glycoprotein (P-gp) is a member of the ATP-Binding Cassette transporter superfamily and mediates transmembrane efflux of many drugs. Since it is involved in multi-drug resistance activity in various cancer cells, the development of P-gp inhibitor is one of the major concerns in anticancer therapy. Human P-gp protein has at least two "functional" drug binding sites that are called "H" site and "R" site, hence it has multi-bindingspecificities. Though the amino acid residues that constitute in drug binding pockets have been proposed by previous experimental evidences, the shapes and the binding poses are not revealed clearly yet. In this study, human P-gp structure was built by homology modeling with available crystal structure of mouse P-gp as a template and docking simulations were performed with inhibitors such as verapamil, hoechst33342, and rhodamine123 to construct the interaction between human P-gp and its inhibitors. The docking simulations were performed 500 times for each inhibitor, and then the interaction frequency of the amino acids at the binding poses was analyzed. With the analysis results, we proposed highly contributing residues that constitute binding pockets of the human P-gp for the inhibitors. Using the highly contributing residues, we proposed the locations and the shapes of verapamil binding site and "R" site, and suggested the possible position of "H" site.

Original languageEnglish
Pages (from-to)2317-2325
Number of pages9
JournalBulletin of the Korean Chemical Society
Volume35
Issue number8
DOIs
Publication statusPublished - 2014 Aug 20

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P-Glycoprotein
Glycoproteins
Pharmaceutical Preparations
Verapamil
Binding Sites
Amino Acids
ATP-Binding Cassette Transporters
Crystal structure
Cells
Proteins

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

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abstract = "P-glycoprotein (P-gp) is a member of the ATP-Binding Cassette transporter superfamily and mediates transmembrane efflux of many drugs. Since it is involved in multi-drug resistance activity in various cancer cells, the development of P-gp inhibitor is one of the major concerns in anticancer therapy. Human P-gp protein has at least two {"}functional{"} drug binding sites that are called {"}H{"} site and {"}R{"} site, hence it has multi-bindingspecificities. Though the amino acid residues that constitute in drug binding pockets have been proposed by previous experimental evidences, the shapes and the binding poses are not revealed clearly yet. In this study, human P-gp structure was built by homology modeling with available crystal structure of mouse P-gp as a template and docking simulations were performed with inhibitors such as verapamil, hoechst33342, and rhodamine123 to construct the interaction between human P-gp and its inhibitors. The docking simulations were performed 500 times for each inhibitor, and then the interaction frequency of the amino acids at the binding poses was analyzed. With the analysis results, we proposed highly contributing residues that constitute binding pockets of the human P-gp for the inhibitors. Using the highly contributing residues, we proposed the locations and the shapes of verapamil binding site and {"}R{"} site, and suggested the possible position of {"}H{"} site.",
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In silico study on the interaction between p-glycoprotein and its inhibitors at the drug binding pocket. / Kim, Namseok; Shin, Jae Min; No, Kyoung Tai.

In: Bulletin of the Korean Chemical Society, Vol. 35, No. 8, 20.08.2014, p. 2317-2325.

Research output: Contribution to journalArticle

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