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- Title
In vitro and in silico evaluation of P‐glycoprotein inhibition through <sup>99m</sup>Tc‐methoxyisobutylisonitrile uptake.
- Authors
Hosseini Balef, Seyed Sajad; Piramoon, Majid; Hosseinimehr, Seyed Jalal; Irannejad, Hamid
- 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 99mTc‐methoxyisobutylisonitrile (MIBI) was used as a P‐gp efflux substrate for calculating IC50 values. Results of the 99mTc‐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 99mTc‐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. Flexible docking could substantially elucidate the main binding space of P‐glycoprotein (P‐gp) substrate or inhibitors, which is located at the tip of the P‐gp funnel‐shaped hydrophobic channel. Results showed that our 99mTc‐methoxyisobutylisonitrile radiotracer–cell‐based assay is an accurate and fast screening tool for detecting P‐gp inhibitors and non‐inhibitors in drug development process.
- Subjects
P-glycoprotein; NITRILE derivatives; MULTIDRUG transporters; MOLECULAR dynamics; MOLECULAR docking; DRUG development
- Publication
Chemical Biology & Drug Design, 2019, Vol 93, Issue 3, p283
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.13411