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

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 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.

• Authors: Anders Bach, Søren W Pedersen, Liam A Dorr, Gary Vallon, Isabelle Ripoche, Sylvie Ducki, Lu-Yun Lian
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 12157 (Jul 16 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26177569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-((1H-benzo(d)(1,2,3)triazol-5-ylamino)methyl)-4,6-dichlorophenol
• Aminosalicylic Acids
• Benzylamines
• Chlorophenols
• DLG4 protein, human
• Disks Large Homolog 4 Protein
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Triazoles
• ZL006 compound
• Nitric Oxide Synthase Type I

Topics

• Aminosalicylic Acids (pharmacology)
• Benzylamines (pharmacology)
• Calorimetry
• Chlorophenols (pharmacology)
• Disks Large Homolog 4 Protein
• Fluorescence Polarization
• Humans
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Magnetic Resonance Spectroscopy
• Membrane Proteins (antagonists & inhibitors)
• Nitric Oxide Synthase Type I (antagonists & inhibitors)
• PDZ Domains (drug effects)
• Triazoles (pharmacology)