Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening

ECHEVERRÍA, EMILIANA; RUEDA, ANA JULIA VELEZ; CABRERA, MAIA; JURITZ, EZEQUIEL; BURGHI, VALERIA; FABIÁN, LUCAS; DAVIO, CARLOS; MENNA, PABLO LORENZANO; FERNÁNDEZ, NATALIA CRISTINA

LIFE SCIENCES

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2019

0024-3205

AimsG protein-coupled receptor (GPCR) kinases (GRKs) are mainly involved in thedesensitization of GPCRs. Among them, GRK2 has been described to beupregulated in many pathological conditions and its crucial role in cardiachypertrophy, hypertension, and heart failure promoted the search forpharmacological 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. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2.Materials and methodsWe performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and Gαq protein. To evaluate the biological activity of compounds we measured, calcium response of histamine H1 receptor (H1R) using Fura-2AM dye and H1Rinternalization by saturation binding experiments in A549 cells. GRK2(45-178)GFPtranslocation was determined in HeLa cells through confocal fluorescence imaging.Key findingsWe identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Alsocandidates presented adequate lipophilia and cytotoxicity profile.