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

Publication date: Available online 13 September 2019Source: Life SciencesAuthor(s): Emiliana Echeverría, Ana Julia Velez Rueda, Maia Cabrera, Ezequiel Juritz, Valeria Burghi, Lucas Fabián, Carlos Davio, Pablo Lorenzano Menna, Natalia Cristina FernándezAbstractAimsG 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. 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 H1R internalization by saturation binding experiments in A549 cells. GRK2(45-178)GFP translocation was determined in HeLa cells through confocal fluorescence imaging.Key findingsWe identified inhibitors ...
Source: Life Sciences - Category: Biology Source Type: research