Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions.
Sci Rep
; 5: 12157, 2015 Jul 16.
Article
en En
| MEDLINE
| ID: mdl-26177569
ABSTRACT
ZL006 and IC87201 have been presented as efficient inhibitors of the nNOS/PSD-95 protein-protein interaction and shown great promise in cellular experiments and animal models of ischemic stroke and pain. Here, we investigate the proposed mechanism of action of ZL006 and IC87201 using biochemical and biophysical methods, such as fluorescence polarization (FP), isothermal titration calorimetry (ITC), and (1)H-(15)N HSQC NMR. Our data show that under the applied in vitro conditions, ZL006 and IC87201 do not interact with the PDZ domains of nNOS or PSD-95, nor inhibit the nNOS-PDZ/PSD-95-PDZ interface by interacting with the ß-finger of nNOS-PDZ. Our findings have implications for further medicinal chemistry efforts of ZL006, IC87201 and analogues, and challenge the general and widespread view on their mechanism of action.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Triazoles
/
Bencilaminas
/
Clorofenoles
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Péptidos y Proteínas de Señalización Intracelular
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Óxido Nítrico Sintasa de Tipo I
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Dominios PDZ
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Ácidos Aminosalicílicos
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Sci Rep
Año:
2015
Tipo del documento:
Article