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

Balef, Seyed Sajad Hosseini and Piramoon, Majid and Hosseinimehr, Seyed Jalal and Irannejad, Hamid (2019) In vitro and in silico evaluation of P-glycoprotein inhibition through Tc-99m-methoxyisobutylisonitrile uptake. CHEMICAL BIOLOGY & DRUG DESIGN, 93 (3). pp. 283-289.

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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 Tc-99m-methoxyisobutylisonitrile (MIBI) was used as a P-gp efflux substrate for calculating IC50 values. Results of the Tc-99m-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 Tc-99m-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 > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine, Health and Life Sciences > School of Medicine
Depositing User: sobhan rezaiian
Date Deposited: 11 Mar 2019 06:13
Last Modified: 11 Mar 2019 06:13
URI: http://eprints.lums.ac.ir/id/eprint/1585

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