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 language | English |
|---|---|
| Pages (from-to) | 2317-2325 |
| Number of pages | 9 |
| Journal | Bulletin of the Korean Chemical Society |
| Volume | 35 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2014 Aug 20 |
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All Science Journal Classification (ASJC) codes
- Chemistry(all)
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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 journal › Article
TY - JOUR
T1 - In silico study on the interaction between p-glycoprotein and its inhibitors at the drug binding pocket
AU - Kim, Namseok
AU - Shin, Jae Min
AU - No, Kyoung Tai
PY - 2014/8/20
Y1 - 2014/8/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84906337309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84906337309&partnerID=8YFLogxK
U2 - 10.5012/bkcs.2014.35.8.2317
DO - 10.5012/bkcs.2014.35.8.2317
M3 - Article
AN - SCOPUS:84906337309
VL - 35
SP - 2317
EP - 2325
JO - Bulletin of the Korean Chemical Society
JF - Bulletin of the Korean Chemical Society
SN - 0253-2964
IS - 8
ER -