title: High-throughput modeling of human G-protein coupled receptors: amino acid sequence alignment, three-dimensional model building, and receptor library screening.
abstract: The current study describes the development of a computer package (GPCRmod) aimed at the high-throughput modeling of the therapeutically important family of human G-protein coupled receptors (GPCRs). GPCRmod first proposes a reliable alignment of the seven transmembrane domains (7 TMs) of most druggable human GPCRs based on pattern/motif recognition for each of the 7 TMs that are considered independently. It then converts the alignment into knowledge-based three-dimensional (3-D) models starting from a set of 3-D backbone templates and two separate rotamer libraries for side chain positioning. The 7 TMs of 277 human GPCRs have been accurately aligned, unambiguously clustered in three different classes (rhodopsin-like, secretin-like, metabotropic glutamate-like), and converted into high-quality 3-D models at a remarkable throughput (ca. 3s/model). A 3-D GPCR target library of 277 receptors has consequently been setup. Its utility for "in silico" inverse screening purpose has been demonstrated by recovering among top scorers the receptor of a selective GPCR antagonist as well as the receptors of a promiscuous antagonist. The current GPCR target library thus constitutes a 3-D database of choice to address as soon as possible the "virtual selectivity" profile of any GPCR antagonist or inverse agonist in an early hit optimization process.
authors.affiliation: Bioinformatics Group, Laboratoire de Pharmacochimie de la Communication Cellulaire (CNRS UMR 7081), 74 Route du Rhin, B.P.24, F-67400 Illkirch, France.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bissantz
authors.forename: Antoine
authors.initials: A
authors.lastname: Logean
authors.forename: Didier
authors.initials: D
authors.lastname: Rognan
mesh_terms: D000595:Amino Acid Sequence; D006801:Humans; D008956:Models, Chemical; D008969:Molecular Sequence Data; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D043562:Receptors, G-Protein-Coupled