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Insights into Selectivity from Rationally Designed Inhibitors of G protein‐coupled Receptor Kinase 2
Author(s) -
Homan Kristoff,
Wilson Michael,
Larsen Scott,
Tesmer John
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1172.2
Subject(s) - paroxetine , chemistry , beta adrenergic receptor kinase , kinase , pharmacology , biophysics , receptor , biochemistry , serotonin , biology , g protein coupled receptor
No small molecule inhibitors selective for G protein‐coupled receptor kinase 2 (GRK2), a validated target for the treatment of heart failure, have advanced to clinical trials. Through the development of a high throughput GRK2‐RNA displacement assay, over 500,000 potential inhibitors have been evaluated. One potential inhibitor of GRK2 of particular interest is the selective serotonin reuptake inhibitor paroxetine. We have shown that paroxetine is capable of inhibiting GRK2 with up to 50‐fold selectivity over other GRKs and mediates increases in contractility in both isolated cardiomyocytes and whole animal studies. Analyses of additional compounds have contributed to the development a structure activity relationship model for compounds based on the paroxetine scaffold. A crystal structure of GRK2 in complex with paroxetine has been used to rationally design derivatives of paroxetine, which effectively decouples the SSRI and kinase inhibition functions of paroxetine without major changes to the scaffold. A newly obtained crystal structure of GRK2 in complex with a paroxetine derivative confirms the feasibility of rational design with the GRK2·paroxetine scaffold. Additional kinetic characterization of derivatives of paroxetine and newly obtained crystallographic complexes containing inhibitors suggest the underlying molecular mechanisms of inhibitor selectivity among AGC family protein kinases.