In vitro and in silico evaluation of P-glycoprotein inhibition through 99m Tc-methoxyisobutylisonitrile uptake

Hosseini Balef, ss and Piramoon, m and Hosseinimehr, sj and Irannejad, h (2018) In vitro and in silico evaluation of P-glycoprotein inhibition through 99m Tc-methoxyisobutylisonitrile uptake. Chem Biol Drug Des..

Full text not available from this repository.
Official URL: https://onlinelibrary.wiley.com/doi/abs/10.1111/cb...

Abstract

P-glycoprotein (P-gp) is a multidrug resistance (MDR) transporter with unknown structural details. This macromolecule is normally responsible for extruding xenobiotics from normal cells. Overexpression of P-gp in tumor cells is a major obstacle in cancer chemotherapy. In this study, human 3D model of P-gp was built by homology modeling based on mouse P-gp crystallographic structure and stabilized through 1 ns molecular dynamics (MD) simulation. Stabilized human P-gp structure was used for flexible docking of 80 drugs into the putative active site of P-gp. Accordingly, digoxin, itraconazole, risperidone, ketoconazole, prazosin, verapamil, cyclosporine A, and ranitidine were selected for further in vitro assay. Subsequently, cell-based P-gp inhibition assay was performed on Caco-2 cells while 99m Tc-methoxyisobutylisonitrile (MIBI) was used as a P-gp efflux substrate for calculating IC50 values. Results of the 99m Tc-MIBI uptake in drug-treated Caco-2 cells were in agreement with the previously reported activities. This study for the first time described the relation between molecular dynamics and flexible docking with cellular experiments using 99m Tc-MIBI radiotracer for evaluation of potencies of P-gp inhibitors. Finally, results showed that our radiotracer-cell-based assay is an accurate and fast screening tool for detecting P-gp inhibitors and non-inhibitors in drug development process.

Item Type: Article
Subjects: Q Science > QD Chemistry
R Medicine > RZ Other systems of medicine
Divisions: Faculty of Medicine, Health and Life Sciences > School of Medicine
Depositing User: sobhan rezaiian
Date Deposited: 27 Nov 2018 07:09
Last Modified: 27 Nov 2018 07:09
URI: http://eprints.lums.ac.ir/id/eprint/1486

Actions (login required)

View Item View Item