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.AbbreviationsABC - 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. |