Forskning ved Københavns Universitet - Københavns Universitet

Forside

Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Bach, Anders*; Pedersen, Søren W.; Dorr, Liam A.; Vallon, Gary; Ripoche, Isabelle; Ducki, Sylvie; Lian, Lu-Yun* (*Corresponding)
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 β-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.
OriginalsprogEngelsk
Artikelnummer12157
TidsskriftScientific Reports
Vol/bind5
Sider (fra-til)1-12
Antal sider12
ISSN2045-2322
StatusUdgivet - 2015

ID: 141733202