title: Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach.
abstract: In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein-ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein-ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb-drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.
authors.affiliation: a Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy , Chiang Mai University , Chiang Mai , Thailand.
authors.forename: Pathomwat
authors.initials: P
authors.lastname: Wongrattanakamon
authors.affiliation: b Department of Chemistry, Faculty of Science , University of Malaya , Kuala Lumpur , Malaysia.
authors.forename: Vannajan Sanghiran
authors.initials: VS
authors.lastname: Lee
authors.affiliation: c Computational Simulation and Modelling Laboratory (CSML), Department of Chemistry, Faculty of Science , Chiang Mai University , Chiang Mai , Thailand.
authors.forename: Piyarat
authors.initials: P
authors.lastname: Nimmanpipug
authors.affiliation: d Department of Pharmaceutical Sciences, Faculty of Pharmacy , Chiang Mai University , Chiang Mai , Thailand.
authors.forename: Busaban
authors.initials: B
authors.lastname: Sirithunyalug
authors.affiliation: d Department of Pharmaceutical Sciences, Faculty of Pharmacy , Chiang Mai University , Chiang Mai , Thailand.
authors.forename: Sunee
authors.initials: S
authors.lastname: Chansakaow
authors.affiliation: a Laboratory for Molecular Design and Simulation (LMDS), Department of Pharmaceutical Sciences, Faculty of Pharmacy , Chiang Mai University , Chiang Mai , Thailand.
authors.forename: Supat
authors.initials: S
authors.lastname: Jiranusornkul
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D005419:Flavonoids / Q000737:chemistry / Q000633:toxicity*; D041743:Herb-Drug Interactions; D006801:Humans; D008024:Ligands; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005419:Flavonoids; D008024:Ligands
keywords: P-glycoprotein; flavonoids; herb–drug interaction; molecular modeling; nucleotide-binding domain 2