title: Comparative docking study of anibamine as the first natural product CCR5 antagonist in CCR5 homology models.
abstract: Anibamine, a novel pyridine quaternary alkaloid recently isolated from Aniba sp., has been found to effectively bind to the chemokine receptor CCR5 with an IC(50) at 1 microM in competition with (125)I-gp120, an HIV viral envelope protein binding to CCR5 with high affinity. Since CCR5, a G-protein-coupled receptor, is an essential coreceptor for the human immunodeficiency virus type I (HIV-1) entry to host cells, a CCR5 antagonist that inhibits the cellular entry of HIV-1 provides a new therapy choice for the treatment of HIV. Anibamine provides a novel structural skeleton that is remarkably different from all lead compounds previously identified as CCR5 antagonists. Here, we report comparative docking studies of anibamine with several other known CCR5 antagonists in two CCR5 homology models built based on the crystal structures of bovine rhodopsin and human beta(2)-adrenergic receptor. The binding pocket of anibamine has some common features shared with other high affinity CCR5 antagonists, suggesting that they may bind in similar binding sites and/or modes. At the same time, several unique binding features of anibamine were identified, and it will likely prove beneficial in future molecular design of novel CCR5 antagonists based on the anibamine scaffold.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298-0540, USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.forename: Kendra M
authors.initials: KM
authors.lastname: Haney
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D002417:Cattle; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D048088:Informatics; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry / Q000235:genetics; D019713:Receptors, CCR5 / Q000737:chemistry / Q000235:genetics; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D011725:Pyridines; D018343:Receptors, Adrenergic, beta-2; D019713:Receptors, CCR5; C488244:anibamine; D012243:Rhodopsin