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

Helen V Waldschmidt; Renee Bouley; Paul D Kirchhoff; Pil Lee; John J G Tesmer; Scott D Larsen

doi:10.1016/j.bmcl.2018.03.082

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

Bioorg Med Chem Lett. 2018 May 15;28(9):1507-1515. doi: 10.1016/j.bmcl.2018.03.082. Epub 2018 Mar 30.

Authors

Helen V Waldschmidt¹, Renee Bouley², Paul D Kirchhoff³, Pil Lee³, John J G Tesmer⁴, Scott D Larsen⁵

Affiliations

¹ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
² Department of Pharmacology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States.
³ Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States.
⁴ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States; Department of Pharmacology and the Life Sciences Institute, University of Michigan, Ann Arbor, MI, United States; Department of Biological Sciences, Purdue University, West Lafayette, IN, United States.
⁵ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States; Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, MI, United States. Electronic address: sdlarsen@umich.edu.

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.

Keywords: Crystallography; Docking; GPCRs; GRKs; Kinases.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Dose-Response Relationship, Drug
G-Protein-Coupled Receptor Kinase 2 / antagonists & inhibitors*
G-Protein-Coupled Receptor Kinase 2 / metabolism
G-Protein-Coupled Receptor Kinase 5 / antagonists & inhibitors*
G-Protein-Coupled Receptor Kinase 5 / metabolism
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Amides
Protein Kinase Inhibitors
GRK2 protein, human
G-Protein-Coupled Receptor Kinase 2
G-Protein-Coupled Receptor Kinase 5
GRK5 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding