Study On The P-glycoprotein Homology Modeling And Molecular-docking Simulation

P-glycoprotein(P-gp, ABCB1)belongs to the family of ATP-binding cassette proteins. The role of the protein which hydrolyzes ATP to detoxify cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance(MDR) in the treatment of cancers. Here we present three-dimentional model of catalytic state of P-glycoprotein by homology modeling, and it was builted based on a wide open nucleotide-free inward-facing conformation of Mus musculus ABCB1.When the model was built, it was further optimized and processed by molecular dynamic simulation, and then PROCHECK, ERRAT and PROSA programs were used for energy and conformation evaluation. As a quality assurance of the P-gp model, Comparied inter-residue Cα-Cαdistances in the human P-gp model with that in the mouse P-gp crystal structure and from experimental cross- linking and site directed mutagenesis data studies on human P-gp. The accuracy of model is conformed in this study.In addition, docked one of human P-glycoprotein's equilibrium conformations with ligands, which include symbolic substrates: Colchicine,Rhodamine123, anti-cancer drugs: Imatinib,Dasatinib,Estramustine,Daunorubicin,Paciltaxel,Docetaxel and its inhibitors: Biricodar, Verapamil, Cyclosporine, Vinblastine, Tamoxifen. All of the ligands with different sizes were successfully docked in. The volume in which the ligands were docked was centered on the geometric center of the residues that experimentally identified to relate with drug specificity. This volume is taken large enough to enclose the large central cavity that runs between the borders with the cytosol and the extracellular medium. Almost 12 TM helices of P-gp take part in binding with ligands, TM1,TM5,TM6,TM7,TM11 and TM12 contribute greatly to the ligand-binding domain. Through analysis of the hydrogen bonding, hydrophobic and electrostatic interactions between P-gp and ligands, it reveals reaction mechanism between P-gp and ligands and also confirms the rationality and reliability of human P-gp model.