Homology modeling and structural analysis of human P-glycoprotein

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.

Homology modelling of human P-glycoprotein

“…They were able to show that derivatives could be designed that inhibited P-gp and also led to an improved in vitro efficacy in a sensitized drug-resistant (to doxorubicin) cell line [27]. Other studies have used docking to explore the binding of potential novel inhibitors such as 6-(methylsulfinyl)hexyl isothiocyanate [28] and guanidine alkaloid [29]. They found in each case that these drugs bind in similar locations to known P-gp inhibitors such as QZ59-RRR [28] and verapamil [29].…”

“…Other studies have used docking to explore the binding of potential novel inhibitors such as 6-(methylsulfinyl)hexyl isothiocyanate [28] and guanidine alkaloid [29]. They found in each case that these drugs bind in similar locations to known P-gp inhibitors such as QZ59-RRR [28] and verapamil [29]. Klepsch et al [30] explored the binding mode of propafenone derivatives in homology models derived from the Sav1866 and mouse crystal structures to capture the differences between the conformational states [30].…”

In vitro and in silico evaluation of P‐glycoprotein inhibition through 99mTc‐methoxyisobutylisonitrile uptake

“…Several molecular mechanisms, which are involved in drug resistance, have been identified, and one is attributed to drug efflux pumps. [3,4] Owing to the polyspecificity in substrate binding and promiscuity in P-gp substrate structural features, developing a pharmacophore model for P-gp substrates or inhibitors has not been performed yet. [1] P-gp is a protein from the ATP binding cassette (ABC) superfamily.…”

On the Origin of Large Flexibility of P-glycoprotein in the Inward-facing State

“…Structural models of Pgp have been used for drug docking to investigate its mechanism of multidrug resistance (5–18). Although the structure of Pgp has been experimentally solved only in the nucleotide-free, inward-facing state, many studies have used homology modeling to construct a model for the ATP-bound, outward-facing conformation based on the SAV1866 structure as a template (5, 6, 14, 15, 19–22).…”