title: Molecular modeling of vasopressin receptor and in silico screening of V1b receptor antagonists.
abstract: BACKGROUND
  G protein-coupled receptors (GPCRs) are integral membrane proteins which contain seven-transmembrane-spanning alpha-helices. GPCR-mediated signaling has been associated with various human diseases, positioning GPCRs as attractive targets in the drug discovery field. Recently, through advances in protein engineering and crystallography, the number of resolved GPCR structures has increased dramatically. This growing availability of GPCR structures has greatly accelerated structure-based drug design (SBDD) and in silico screening for GPCR-targeted drug discovery.
  
  
  METHODS
  The authors introduce the current status of X-ray crystallography of GPCRs and what has been revealed from the resolved crystal structures. They also review the recent advances in SBDD and in silico screening for GPCR-targeted drug discovery and discuss a docking study, using homology modeling, with the discovery of potent antagonists of the vasopressin 1b receptor.
  
  
  CONCLUSIONS
  Several innovative protein engineering techniques and crystallographic methods have greatly accelerated SBDD, not only for already-resolved GPCRs but also for those structures which remain unclear. These technological advances are expected to enable the determination of GPCR-fragment complexes, making it practical to perform fragment-based drug discovery. This paves the way for a new era of GPCR-targeted drug discovery.
authors.affiliation: Drug Discovery Research, Astellas Pharma, Inc., 21, Miyukigaoka, Ibaraki 305-8585, Japan. masaya.orita@jp.astellas.com
authors.forename: Yohsuke
authors.initials: Y
authors.lastname: Hagiwara
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ohno
authors.forename: Masazumi
authors.initials: M
authors.lastname: Kamohara
authors.forename: Jun
authors.initials: J
authors.lastname: Takasaki
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Fukunishi
authors.forename: Haruki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
mesh_terms: D000818:Animals; D003198:Computer Simulation; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D043562:Receptors, G-Protein-Coupled