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In vitro and in silico evaluation of P-glycoprotein inhibition through 99m Tc-methoxyisobutylisonitrile uptake.
- Source :
-
Chemical biology & drug design [Chem Biol Drug Des] 2019 Mar; Vol. 93 (3), pp. 283-289. Date of Electronic Publication: 2018 Oct 21. - Publication Year :
- 2019
-
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 <superscript>99m</superscript> Tc-methoxyisobutylisonitrile (MIBI) was used as a P-gp efflux substrate for calculating IC50 values. Results of the <superscript>99m</superscript> 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 <superscript>99m</superscript> 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.<br /> (© 2018 John Wiley & Sons A/S.)
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Binding Sites
Caco-2 Cells
Drug Resistance, Neoplasm
Humans
Inhibitory Concentration 50
Molecular Docking Simulation
Organotechnetium Compounds metabolism
Protein Structure, Tertiary
Radiopharmaceuticals metabolism
ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Organotechnetium Compounds chemistry
Radiopharmaceuticals chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1747-0285
- Volume :
- 93
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Chemical biology & drug design
- Publication Type :
- Academic Journal
- Accession number :
- 30270513
- Full Text :
- https://doi.org/10.1111/cbdd.13411