Finding of novel GRK2 inhibitors

G protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in the desensitization of GPCRs. Among them, GRK2 has been described to be upregulated in many pathological conditions and its crucial role in cardiac hypertrophy, hypertension, and heart failure promoted the search for pharmacological inhibitors of its activity. There have been several reports of potent and selective inhibitors of GRK2, most of them directed to the kinase domain of the protein. However, the homologous to the regulator of G protein signaling (RH) domain of GRK2 has also been shown to regulate GPCRs signaling. In this work, researchers from the Laboratory of Signal Transduction and Drug Design, in collaboration with people at the University of Quilmes, searched for potential inhibitors of receptor desensitization mediated by the RH domain of GRK2. Performing a docking-based virtual screening utilizing the crystal structure of GRK2 they searched for potential inhibitors of the interaction between GRK2 and Gαq protein. In this work, they identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to the plasma membrane. These molecules can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.