title: Molecular dynamics simulation and molecular docking studies of 1,4-Dihydropyridines as P-glycoprotein's allosteric inhibitors.
abstract: P-glycoprotein (P-gp) is a main factor contributing to multidrug resistance. The effect of this transporter protein on limiting the effectiveness of chemotherapy has been shown by various studies. In a previous report, we synthesized some 14-dihydropyridine (DHP) derivatives as inhibitors of human P-gp. In the present study, a computational approach has been exploited to reveal the main interactions between DHPs and P-gp. In order to do this, homology modeling was performed to obtain a model of the protein. Then, molecular dynamics simulation was used to refine the constructed model of P-gp in the presence of the lipids bilayer. Model validation was performed with several tools. Finally, molecular docking followed by MD simulation of ligand-protein complex was employed to elucidate the binding mode and the dynamical changes of protein with/without DHPs bound. The results emphasized that interaction of the residues Gln912, Ser909, Arg905, Ser474, Val472 with DHPs play a crucial role in the inhibitory of these ligands and this was in a relatively good accordance with the results reported in the experimental studies.
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.|b Department of Medicinal Chemistry, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Omolbanin
authors.initials: O
authors.lastname: Shahraki
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Farshid
authors.initials: F
authors.lastname: Zargari
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Najmeh
authors.initials: N
authors.lastname: Edraki
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.|b Department of Medicinal Chemistry, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Khoshneviszadeh
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Omidreza
authors.initials: O
authors.lastname: Firuzi
authors.affiliation: a Medicinal and Natural Products Chemistry Research Center , Shiraz University of Medical Sciences , Shiraz , Iran.
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D004095:Dihydropyridines / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004095:Dihydropyridines; C038806:1,4-dihydropyridine
keywords: P-glycoprotein; dihydropyridine; molecular docking; molecular dynamics simulation