AAPS PharmSci

, Volume 2, Issue 1, pp 9–21 | Cite as

Molecular modeling of G-protein coupled receptor kinase 2: Docking and biochemical evaluation of inhibitors

  • Matthias U. Kassack
  • Petra Högger
  • Daniel A. Gschwend
  • Kimihiko Kameyama
  • Tatsuya Haga
  • Richard C. Graul
  • Wolfgang Sadée


G-protein coupled receptor kinase 2 (GRK2) regulates the activity of many receptors. Because potent inhibitors of GRK2 are thus far limited to polyanionic compounds like heparin, we searched for new inhibitors with the aid of a molecular model of GRK2. We used the available crystal structure of cAMP dependent protein kinase (cAPK) as a template to construct a 3D homology model of GRK2. Known cAPK and GRK2 inhibitors were docked into the active sites of GRK2 and cAPK using DOCK v3.5. H8 docked into the hydrophobic pocket of the adenosine 5-triphosphate (ATP) binding site of cAPK, consistent with its known competitive cAPK inhibition relative to ATP. Similarly, 3 of 4 known GRK2 inhibitors docked into the ATP binding pocket of GRK2 with good scores. Screening the Fine Chemicals Directory (FCD, containing the 3D structures of 13,000 compounds) for docking into the active sites of GRK2 identified H8 and the known GRK2 inhibitor trifluoperazine as candidates. Whereas H8 indeed inhibited light-dependent phosphorylation of rhodopsin by GRK2, but with low potency, 3 additional FCD compounds with promising GRK2 scores failed to inhibit GRK2. This result demonstrates limitations of the GRK2 model in predicting activity among diverse chemical structures. Docking suramin, an inhibitor of protein kinase C (not present in FCD) yielded a good fit into the ATP binding site of GRK2 over cAPK. Suramin did inhibit GRK2 with IC50 32 μM (pA2 6.39 for competitive inhibition of ATP). Suramin congeners with fewer sulfonic acid residues (NF062, NF503 [IC50 14 μM]) or representing half of the suramin molecule (NF520) also inhibited GRK2 as predicted by docking. In conclusion, suramin and analogues are lead compounds in the development of more potent and selective inhibitors of GRK2.


Suramin Docking Score AAPS PharmSci Adenine Ring Catalytic Loop 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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Copyright information

© American Association of Pharmaceutical Scientists 2002

Authors and Affiliations

  • Matthias U. Kassack
    • 1
  • Petra Högger
    • 2
  • Daniel A. Gschwend
    • 3
  • Kimihiko Kameyama
    • 4
  • Tatsuya Haga
    • 4
  • Richard C. Graul
    • 1
  • Wolfgang Sadée
    • 1
  1. 1.Department of Biopharmaceutical Sciences and Pharmaceutical ChemistryUniversity of California San FranciscoSan Francisco
  2. 2.Institute of Pharmaceutical ChemistryWestfälische Wilhelms UniversitätMünsterGermany
  3. 3.Department of Molecular and Cellular BiologyHarvard UniversityCambridge
  4. 4.Department of Neurochemistry, Faculty of MedicineUniversity of TokyoTokyoJapan

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