title: New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding.
abstract: Bradykinin (BK) is a nonapeptide involved in several pathophysiological conditions including among others, septic and haemorrhagic shock, anaphylaxis, arthritis, rhinitis, asthma, inflammatory bowel disease. Accordingly, BK antagonists have long been sought after for therapeutic intervention. Action of BK is mediated through two different G-protein coupled receptors known as B1 and B2. Although there are several B1 antagonists reported in literature, their pharmacological profile is not yet optimal so that new molecules need to be discovered. In the present work we have constructed an atomistic model of the B1 receptor and docked diverse available non-peptide antagonists in order to get a deeper insight into the structure-activity relationships involving binding to this receptor. The model was constructed by homology modeling using the chemokine CXC4 and bovine rhodopsin receptors as template. The model was further refined using molecular dynamics for 600ns with the protein embedded in a POPC bilayer. From the refinement process we obtained an average structure that was used for docking studies using the Glide software. Antagonists selected for the docking studies include Compound 11, Compound 12, Chroman28, SSR240612, NPV-SAA164 and PS020990. The results of the docking study underline the role of specific receptor residues in ligand binding. The results of this study permitted to define a pharmacophore that describes the stereochemical requirements of antagonist binding, and can be used for the discovery of new compounds.
authors.affiliation: Dept. of Chemical Engineering, Universitat Politecnica de Catalunya, ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain.
authors.forename: Cecylia S
authors.initials: CS
authors.lastname: Lupala
authors.affiliation: Dept. of Chemical Engineering, Universitat Politecnica de Catalunya, ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gomez-Gutierrez
authors.affiliation: Dept. of Chemical Engineering, Universitat Politecnica de Catalunya, ETSEIB. Av. Diagonal, 647, 08028 Barcelona, Spain. Electronic address: juan.jesus.perez@upc.edu.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Perez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D065169:Bradykinin B1 Receptor Antagonists / Q000737:chemistry*; D002417:Cattle; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011485:Protein Binding; D043783:Receptor, Bradykinin B1 / Q000737:chemistry; D016415:Sequence Alignment; D013237:Stereoisomerism
chemical_list: D065169:Bradykinin B1 Receptor Antagonists; D043783:Receptor, Bradykinin B1
keywords: B1 antagonist; Bradykinin B1 receptor; GPCR homology modeling; Pharmacophore development