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Title

Homology modeling and structural analysis of human P-glycoprotein

 

Authors

Hideaki Yamaguchi1*, Yumi Kidachi2, Katsuyoshi Kamiie2, Toshiro Noshita3 & Hironori Umetsu4

 

Affiliation

1Department of Pharmacy, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpaku, Nagoya 468-8503, Japan; 2Department of Pharmacy, Faculty of Pharmaceutical Sciences, Aomori University, 2-3-1 Kobata, Aomori 030-0943, Japan; 3Department of Life Sciences, Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, 562 Nanatsuka, Shobara 727-0023, Japan; 4Laboratory of Food Chemistry, Department of Life Sciences, Junior College, Gifu Shotoku Gakuen University, 1-38 Nakauzura, Gifu 055-8288, Japan.

 

Email

hyamagu@meijo-u.ac.jp; *Corresponding author

 

Article Type

Hypothesis

 

Date

Received October 22, 2012; Accepted October 26, 2012; Published November 13, 2012

 

Abstract

Homology modeling and structural analysis of human P-glycoprotein (hP-gp) were performed with a software package the Molecular Operating Environment (MOE). A mouse P-gp (mP-gp; PDB code: 3G5U) was selected as a template for the 3D structure modeling of hP-gp. The modeled hP-gp showed significant 3D similarities at the drug biding site (DBS) to the mP-gp structure. The contact energy profiles of the hP-gp model were in good agreement with those of the mP-gp structure. Ramachandran plots revealed that only 3.5% of the amino acid residues were in the disfavored region for hP-gp. Further, docking simulations between 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) and the P-gp models revealed the similarity of the ligand-receptor bound location between the hP-gp and mP-gp models. These results indicate that the hP-gp model was successfully modeled and analyzed. To the best of our knowledge, this is the first report of a hP-gp model with a naturally occurring isothiocyanate, and our data verify that the model can be utilized for application to target hP-gp for the development of antitumor drugs.

 

Keywords

Antitumor drug, MOE, P-gp, 6-MITC.

 

Abbreviations

ABC: ATP-binding cassette, ASE-Dock: alpha sphere and excluded volume-based ligand-protein docking, DBS: drug biding site, MDR: multidrug resistance, MOE: Molecular Operating Environment, ITC: isothiocyanate, P-gp: P-glycoprotein.

 

Citation

Yamaguchi et al. Bioinformation 8(22): 1066-1074 (2012)
 

Edited by

P Kangueane

 

ISSN

0973-2063

 

Publisher

Biomedical Informatics

 

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.