In silico Study on the Interaction between P-glycoprotein and Its Inhibitors at the Drug Binding Pocket

Abstract

P-glycoprotein (P-gp) is a member of the ATP-Binding Cassette transporter superfamily and mediates transmembrane efflux of many drugs. Since it is involved in multi-drug resistance activity in various cancer cells, the development of P-gp inhibitor is one of the major concerns in anticancer therapy. Human P-gp protein has at least two "functional" drug binding sites that are called "H" site and "R" site, hence it has multi-bindingspecificities. Though the amino acid residues that constitute in drug binding pockets have been proposed by previous experimental evidences, the shapes and the binding poses are not revealed clearly yet. In this study, human P-gp structure was built by homology modeling with available crystal structure of mouse P-gp as a template and docking simulations were performed with inhibitors such as verapamil, hoechst33342, and rhodamine123 to construct the interaction between human P-gp and its inhibitors. The docking simulations were performed 500 times for each inhibitor, and then the interaction frequency of the amino acids at the binding poses was analyzed. With the analysis results, we proposed highly contributing residues that constitute binding pockets of the human P-gp for the inhibitors. Using the highly contributing residues, we proposed the locations and the shapes of verapamil binding site and "R" site, and suggested the possible position of "H" site.

Homology modeling and substrate binding studies of human P-glycoprotein

“…There were some binding residues that contacted with rhodamine B presenting in Hoechst 33342 binding pocket. A similar observation was also reported by Kim et al 27 , where they observed the top-ranked docking Hoechst 33342 poses interacted with the assigned R-site. Fluorescence resonance energy transfer (FRET) studies pointed out that the Hoechst 33342 binding site is likely located 10−14 Å below the membrane surface, within the cytoplasmic leaflet of the membrane 28 .…”

Achillin Increases Chemosensitivity to Paclitaxel, Overcoming Resistance and Enhancing Apoptosis in Human Hepatocellular Carcinoma Cell Line Resistant to Paclitaxel (Hep3B/PTX)

“…To have greater confidence in the results obtained by our molecular docking method, we evaluate it with three known P-glycoprotein-binding compounds: verapamil, Rhodamine123, and Hoechst 33342. As a crystal structure of one of the most-studied ligand binders of P-glycoprotein is unavailable, we based our results in the interaction residues of each ligand with the two models of hP-gp; many works have been done in this manner [36,37,41]. In Figure 13, the best poses of each ligand in this study over the mP-gp model are displayed.…”

“…In this work, we used two approximations for the homology modeling, one considering the sequence homology, and the other considering the structural features of the TM helices. For the first case, we employed the crystal structure of mus musculus P-glycoprotein (mP-gp) as a template (PDB:3G61) for the construction of the homology model, because of the high sequence homology (83%) between this protein and human P-glycoprotein (hP-gp), an approximation used by Namseok Kim et al [36]. On the other hand, Safiulla Basha et al used the crystal structure of Caenorhabditis elegans P-glycoprotein (cP-gp) as a template (PDB:4F4C) for the construction of the homology model, which has a sequence homology of 46% compared to hP-gp, because of the more reliable orientation of the TM3, TM4, and TM5 helices [37].…”

Predicting ADME Properties of Chemicals

“…Homology model-based study provides theoretical suggestions on probable binding poses and sites (Klepsch et al 2011). Recently, with the binding pocket structure obtained from the homology modeled P-gP structure, four probable binding sites were proposed (Kim et al 2014b).…”