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小分子ZL006和IC87201作为nNOS-PDZ/PSD-95-PDZ相互作用潜在抑制剂的作用机制的生化研究。

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

作者信息

Bach Anders, Pedersen Søren W, Dorr Liam A, Vallon Gary, Ripoche Isabelle, Ducki Sylvie, Lian Lu-Yun

机构信息

Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

NMR Centre for Structural Biology, University of Liverpool, UK L69 7ZB Liverpool.

出版信息

Sci Rep. 2015 Jul 16;5:12157. doi: 10.1038/srep12157.

DOI:10.1038/srep12157
PMID:26177569
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4503980/
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.

摘要

ZL006和IC87201已被证明是nNOS/PSD - 95蛋白质 - 蛋白质相互作用的有效抑制剂，并且在缺血性中风和疼痛的细胞实验及动物模型中显示出巨大潜力。在此，我们使用生化和生物物理方法，如荧光偏振（FP）、等温滴定量热法（ITC）和（1）H - （15）N HSQC NMR，来研究ZL006和IC87201的作用机制。我们的数据表明，在所应用的体外条件下，ZL006和IC87201不与nNOS或PSD - 95的PDZ结构域相互作用，也不通过与nNOS - PDZ的β - 指结构相互作用来抑制nNOS - PDZ/PSD - 95 - PDZ界面。我们的研究结果对ZL006、IC87201及其类似物的进一步药物化学研究具有启示意义，并对它们作用机制的普遍和广泛观点提出了挑战。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/820ba193a9d9/srep12157-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/06c6f12f9817/srep12157-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/2ebc258996d1/srep12157-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/4146dad38fb1/srep12157-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/c90867669a23/srep12157-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/7bd726aaffcb/srep12157-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/820ba193a9d9/srep12157-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/06c6f12f9817/srep12157-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/2ebc258996d1/srep12157-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/4146dad38fb1/srep12157-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/c90867669a23/srep12157-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/7bd726aaffcb/srep12157-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6198/4503980/820ba193a9d9/srep12157-f6.jpg

相似文献

[1]
Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions.

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[7]
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[8]
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引用本文的文献

[1]
Exploring NMDAR pathways in ischemic stroke: implications for neurotoxic and neuroprotective mechanisms and therapeutic strategies.

Naunyn Schmiedebergs Arch Pharmacol. 2025-6-10

[2]
Post-stroke effects of IC87201 on neurobehavioral function and brain injuries: A stereological study.

IBRO Neurosci Rep. 2024-11-24

[3]
GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases.

Pharmaceuticals (Basel). 2023-10-30

[4]
Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation.

Molecules. 2023-9-19

[5]
Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.

Int J Mol Sci. 2023-3-21

[6]
Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

Int J Mol Sci. 2022-9-7

[7]
Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions.

Signal Transduct Target Ther. 2022-7-6

[8]
Modeling rapid and selective capture of nNOS-PSD-95 uncouplers from Sanhuang Xiexin decoction by novel molecularly imprinted polymers based on metal-organic frameworks.

RSC Adv. 2020-2-21

[9]
Targeting receptor complexes: a new dimension in drug discovery.

Nat Rev Drug Discov. 2020-12

[10]
Nitric Oxide Synthase Inhibitors into the Clinic at Last.

Handb Exp Pharmacol. 2021

本文引用的文献

[1]
Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction.

Neurochem Int. 2014-12

[2]
Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke.

J Neurosci. 2014-10-1

[3]
Chemistry: Chemical con artists foil drug discovery.

Nature. 2014-9-25

[4]
Molecular architecture of mammalian nitric oxide synthases.

Proc Natl Acad Sci U S A. 2014-9-2

[5]
Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to-ester mutations.

Nat Commun. 2014

[6]
Excitotoxicity and stroke: identifying novel targets for neuroprotection.

Prog Neurobiol. 2014-4

[7]
Structure-based design of PDZ ligands as inhibitors of 5-HT(2A) receptor/PSD-95 PDZ1 domain interaction possessing anti-hyperalgesic activity.

ACS Chem Biol. 2013-8-23

[8]
Probing the role of backbone hydrogen bonds in protein-peptide interactions by amide-to-ester mutations.

J Am Chem Soc. 2013-6-7

[9]
The nNOS-p38MAPK pathway is mediated by NOS1AP during neuronal death.

J Neurosci. 2013-5-8

[10]
Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice.

Neuropsychopharmacology. 2013-2-27

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