Diseño racional de inhibidores de la actividad RGS de GRK2
GRK2 overexpression is involved in the development of several pathologies with unsatisfied therapeutic demand. Plenty evidences demonstrate a desensitizating mechanism for GPCRs, associated to GRK2 RGS homology domain, and independent of its kinase domain. Since GRK2 potential as therapeutic target...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_5773 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_5773.dir/5773.PDF |
| Aporte de: |
| Sumario: | GRK2 overexpression is involved in the development of several pathologies with unsatisfied therapeutic demand. Plenty evidences demonstrate a desensitizating mechanism for GPCRs, associated to GRK2 RGS homology domain, and independent of its kinase domain. Since GRK2 potential as therapeutic target could lie on its RGS activity, we performed a virtual screening of Enamine library, setting a docking on its RH domain. From 13 compounds (C1-C13) with acceptable in silico binding energies, 4 exerted in vitro activity. C2, C3, C4 and C5 potentiated H2r cAMP response, inhibited GRK2 membrane translocation induced by receptor overexpression, and inhibited coinmunoprecipitation of GRK2 with G?s. We evaluated preliminarily their ADMET properties, and observed that all 4 hits have a suitable lipophilicity, but C3 and C5 stood out, as they didn´t affect cellular viability. After discarding C5 because it also potentiated H1r calcium response, C3 was defined as prototype for analogs design. From those analogs synthesized and evaluated in vitro, we found one that inhibited RGS GRK2 activity by potentiating H2r AMPc response. This compounds could be useful in elucidating other RH functions, and in the future, they could lay the foundation for pharmacologic therapy of those diseases where GRK2 activity is exacerbated. |
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