Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Michigan, Ann Arbor
  • Purdue University

Details

Original languageEnglish (US)
Pages (from-to)1507-1515
Number of pages9
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number9
StatusPublished - May 15 2018
Peer-reviewedYes

Abstract

G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2–Gβγ·GSK180736A and GRK5·CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2.

    Research areas

  • Crystallography, Docking, GPCRs, GRKs, Kinases

Citation formats

APA

Waldschmidt, H. V., Bouley, R., Kirchhoff, P. D., Lee, P., Tesmer, J. J. G., & Larsen, S. D. (2018). Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors. Bioorganic and Medicinal Chemistry Letters, 28(9), 1507-1515. https://doi.org/10.1016/j.bmcl.2018.03.082

Harvard

Waldschmidt, HV, Bouley, R, Kirchhoff, PD, Lee, P, Tesmer, JJG & Larsen, SD 2018, 'Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 28, no. 9, pp. 1507-1515. https://doi.org/10.1016/j.bmcl.2018.03.082