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

LIFE SCIENCES

卷:239

Article

Echeverria, Emiliana¹  Velez Rueda, Ana Julia²  Cabrera, Maia³  Juritz, Ezequiel⁴  Burghi, Valeria¹  Fabian, Lucas⁵  Davio, Carlos¹  Lorenzano Menna, Pablo^3,6,7  Cristina Fernandez, Natalia¹ 

[1] UBA, Inst Invest Farmacol, Fac Farm & Bioquim, ININFA,CONICET, Buenos Aires, DF, Argentina

[2] Natl Univ Quilmes, Dept Sci & Technol, Struct Bioinformat Grp, CONICET, Roque Saenz Pena 352, RA-1876 Bernal, Buenos Aires, Argentina

[3] Univ Nacl Quilmes, Dept Ciencia & Tecnol, Lab Farmacol Mol, CONICET, Roque Saenz Pena 352,B1876BXD, Bernal, Buenos Aires, Argentina

[4] Univ Andres Bello, Fac Ciencias Vida, Ctr Bioinformat & Integrat Biol, Santiago 8370146, Chile

[5] UBA, Fac Farm & Bioquim, Inst Quim & Metab Farmaco, IQUIMEFA,CONICET, Buenos Aires, DF, Argentina

[6] UNR, MPLbioR, Max Planck Lab Struct Biol Chem & Mol Biophys Ros, MPIbpC, S2002LRK, Rosario, Santa Fe, Argentina

[7] UNR, Inst Invest Descubrimiento Farmacos Rosario, IIDEFAR, CONICET, S2002LRK, Rosario, Santa Fe, Argentina

关键词: GRK2;    GPCR;    DBVS;    CADD;    RH;    PPI;   

DOI  :  10.1016/j.lfs.2019.116872

来源: Elsevier

【 摘 要 】

Aims: 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. Herein, we searched for potential inhibitors of receptor desensitization mediated by RH domain of GRK2. Materials and methods: We performed a docking-based virtual screening utilizing the crystal structure of GRK2 to search for potential inhibitors of the interaction between GRK2 and G alpha q 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 findings: We identified inhibitors of GRK2 able to reduce the RH mediated desensitization of the histamine H1 receptor and GRK2 translocation to plasma membrane. Also candidates presented adequate lipophilia and cytotoxicity profile. Significance: We obtained compounds with the ability of reducing RH mediated actions of GRK2 that can be useful as a starting point in the development of novel drug candidates aimed to treat pathologies were GRK2 plays a key role.

【 授权许可】

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