title: Binding of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5: a molecular modeling-guided mutagenesis study of the binding pocket.
abstract: The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template [Palczewski, K., et al. (2000) Science 289, 739-745]. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 [Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644].
authors.affiliation: Department of Molecular SystemsMerck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065, USA. laurie_castonguay@merck.com
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Castonguay
authors.forename: Youmin
authors.initials: Y
authors.lastname: Weng
authors.forename: William
authors.initials: W
authors.lastname: Adolfsen
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.forename: Ruth
authors.initials: R
authors.lastname: Kilburn
authors.forename: Charles G
authors.initials: CG
authors.lastname: Caldwell
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Daugherty
authors.forename: Paul E
authors.initials: PE
authors.lastname: Finke
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Hale
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lynch
authors.forename: Sander G
authors.initials: SG
authors.lastname: Mills
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Martin S
authors.initials: MS
authors.lastname: Springer
authors.forename: Julie A
authors.initials: JA
authors.lastname: DeMartino
mesh_terms: D000409:Alanine / Q000235:genetics; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive / Q000235:genetics; D002073:Butanes / Q000737:chemistry*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010880:Piperidines / Q000737:chemistry*; D017433:Protein Structure, Secondary / Q000235:genetics; D011759:Pyrrolidines / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D019713:Receptors, CCR5 / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D002073:Butanes; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D012243:Rhodopsin; C119369:TAK 779; D000409:Alanine