title: A Strategy Combining Differential Low-Throughput Screening and Virtual Screening (DLS-VS) Accelerating the Discovery of new Modulators for the Orphan GPR34 Receptor.
abstract: The DLS-VS strategy was developed as an integrated method for identifying chemical modulators for orphan GPCRs. It combines differential low-throughput screening (DLS) and virtual screening (VS). The two cascaded techniques offer complementary advantages and allow the experimental testing of a minimal number of compounds. First, DLS identifies modulators specific for the considered receptor among a set of receptors, through the screening of a small library with diverse chemical compounds. Then, an active molecular model of the receptor is built by homology to a validated template, and it is progressively refined by rotamers modification for key side-chains, by VS of the already screened library, and by iterative selection of the model generating the best enrichment. The refined active model is finally used for the VS of a large chemical library and the selection of a small set of compounds for experimental testing. Applied to the orphan receptor GPR34, the DLS-VS strategy combined the experimental screening of 20 000 compounds and the virtual screening of 1 250 000 compounds. It identified one agonist and eight inverse agonists, showing a high chemical diversity. We describe the method. The strategy can be applied to other GPCRs.
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156. constantino.diaz@sanofi.com.
authors.forename: Constantino
authors.initials: C
authors.lastname: Diaz
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Christine
authors.initials: C
authors.lastname: Labit-Le Bouteiller
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Yvon
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Aimée
authors.initials: A
authors.lastname: Cambon-Kernëis
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Annette
authors.initials: A
authors.lastname: Roasio
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Jamme
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Amélie
authors.initials: A
authors.lastname: Aries
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Claude
authors.initials: C
authors.lastname: Feuillerat
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Eric
authors.initials: E
authors.lastname: Perret
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Fréderique
authors.initials: F
authors.lastname: Guette
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Pierre
authors.initials: P
authors.lastname: Dieu
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Miloux
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Danielle
authors.initials: D
authors.lastname: Albène
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Hasel
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Mourad
authors.initials: M
authors.lastname: Kaghad
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Ferran
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Jan
authors.initials: J
authors.lastname: Lupker
authors.affiliation: Sanofi-Aventis Recherche & Développement, Centre de Toulouse, 195 Route d'Espagne, 31036 Toulouse, France fax: +33534632156.
authors.forename: Pascual
authors.initials: P
authors.lastname: Ferrara
keywords: Differential analysis; GPCR; GPR34; Low-throughput screening; Molecular modeling; Virtual screening