title: Cell-based and virtual fragment screening for adrenergic α2C receptor agonists.
abstract: Fragment-based drug discovery has emerged as an alternative to conventional lead identification and optimization strategies generally supported by biophysical detection techniques. Membrane targets like G protein-coupled receptors (GPCRs), however, offer challenges in lack of generic immobilization or stabilization methods for the dynamic, membrane-bound supramolecular complexes. Also modeling of different functional states of GPCRs proved to be a challenging task. Here we report a functional cell-based high concentration screening campaign for the identification of adrenergic α2C receptor agonists compared with the virtual screening of the same ligand set against an active-like homology model of the α2C receptor. The conventional calcium mobilization-based assay identified active fragments with a similar incidence to several other reported fragment screens on GPCRs. 16 out of 3071 screened fragments turned out as specific ligands of α2C, two of which were identified by virtual screening as well and several of the hits possessed surprisingly high affinity and ligand efficiency. Our results indicate that in vitro biological assays can be utilized in the fragment hit identification process for GPCR targets.
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Edit
authors: E
authors: Szőllősi
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Amrita
authors: A
authors: Bobok
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: László
authors: L
authors: Kiss
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Márton
authors: M
authors: Vass
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Dalma
authors: D
authors: Kurkó
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: Sándor
authors: S
authors: Kolok
authors: Gedeon Richter Plc., Gyömrői út 19-21, Budapest H-1103, Hungary.
authors: András
authors: A
authors: Visegrády
authors: Research Centre for Natural Sciences of the Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest H-1117, Hungary.
authors: György M
authors: GM
authors: Keserű
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D011487:Protein Conformation; D018341:Receptors, Adrenergic, alpha-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: C547774:ADRA2C protein, human; D058647:Adrenergic alpha-2 Receptor Agonists; D008024:Ligands; D018341:Receptors, Adrenergic, alpha-2
keywords: Adrenergic agonist; Functional assay; High concentration screening; Virtual screening; α(2C) agonist