title: Insight into the binding model of new antagonists of kappa receptor using docking and molecular dynamics simulation.
abstract: PF-4455242 and its analogues represent a new series of kappa opioid selective antagonists that demonstrate high selectivity and potency. We investigated their binding mode to the κ-receptor via docking and molecular dynamics simulations. The ranking of the predicted binding free energies is consistent with experimental results. Detailed binding free energies between antagonists and individual protein residues were calculated, and key residues involved in binding were identified. Deviation of the active site residues was investigated, and the results show that Gln115, Leu135, Tyr139, Trp287 and Tyr313 deviate greatly from the reference structure. Information obtained from molecular modeling studies will aid in the design of potent kappa receptor antagonists.
authors.affiliation: Key Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
authors.forename: Shiyuan
authors.initials: S
authors.lastname: Hu
authors.forename: Haijing
authors.initials: H
authors.lastname: Yu
authors.forename: Yongjuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tian
authors.initials: T
authors.lastname: Xue
authors.forename: Huabei
authors.initials: H
authors.lastname: Zhang
mesh_terms: D020816:Amino Acid Motifs; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009292:Narcotic Antagonists / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: C568463:2-methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine; D001713:Biphenyl Compounds; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D013449:Sulfonamides