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Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand
Excitotoxicity related to the dysfunction of the N-methyl-d-aspartate receptor (NMDAR) has been indicated to play an integral role in the pathophysiology of multiple disease states, including neurodegenerative disorders such as Parkinson’s disease. There is a notable gap in the market for novel NMDA...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891720/ https://www.ncbi.nlm.nih.gov/pubmed/31766120 http://dx.doi.org/10.3390/molecules24224092 |
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author | Ndzibongwana, Sethu Ngobese, Samukelo Sayed, Ahmad Shongwe, Ciniso White-Phillips, Simon Joubert, Jacques |
author_facet | Ndzibongwana, Sethu Ngobese, Samukelo Sayed, Ahmad Shongwe, Ciniso White-Phillips, Simon Joubert, Jacques |
author_sort | Ndzibongwana, Sethu |
collection | PubMed |
description | Excitotoxicity related to the dysfunction of the N-methyl-d-aspartate receptor (NMDAR) has been indicated to play an integral role in the pathophysiology of multiple disease states, including neurodegenerative disorders such as Parkinson’s disease. There is a notable gap in the market for novel NMDAR antagonists, however current methods to analyse potential antagonists rely on indirect measurements of calcium flux and hazardous radioligand binding assays. Recently, a fluorescent NMDAR ligand, N-adamantan-1-yl-dimethylamino-1-naphthalenesulfonic acid, known as AM-DAN was developed by our group. Additional studies on this ligand is necessary to evaluate its potential as a biological tool in NMDAR research. Therefore, this study was aimed at conducting structural analyses, fluorescence experiments, high-accuracy NMDAR molecular modelling and NMDAR phencyclidine (PCP) site competition binding studies using AM-DAN. Results revealed that AM-DAN has appropriate structural properties, significant fluorescent ability in various solvents and is able to bind selectively and compete for the PCP-binding site of the NMDAR. Therefore, AM-DAN holds promise as a novel fluorescent ligand to measure the affinity of prospective drugs binding at the NMDAR PCP-site and may circumvent the use of radioligands. |
format | Online Article Text |
id | pubmed-6891720 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68917202019-12-12 Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand Ndzibongwana, Sethu Ngobese, Samukelo Sayed, Ahmad Shongwe, Ciniso White-Phillips, Simon Joubert, Jacques Molecules Article Excitotoxicity related to the dysfunction of the N-methyl-d-aspartate receptor (NMDAR) has been indicated to play an integral role in the pathophysiology of multiple disease states, including neurodegenerative disorders such as Parkinson’s disease. There is a notable gap in the market for novel NMDAR antagonists, however current methods to analyse potential antagonists rely on indirect measurements of calcium flux and hazardous radioligand binding assays. Recently, a fluorescent NMDAR ligand, N-adamantan-1-yl-dimethylamino-1-naphthalenesulfonic acid, known as AM-DAN was developed by our group. Additional studies on this ligand is necessary to evaluate its potential as a biological tool in NMDAR research. Therefore, this study was aimed at conducting structural analyses, fluorescence experiments, high-accuracy NMDAR molecular modelling and NMDAR phencyclidine (PCP) site competition binding studies using AM-DAN. Results revealed that AM-DAN has appropriate structural properties, significant fluorescent ability in various solvents and is able to bind selectively and compete for the PCP-binding site of the NMDAR. Therefore, AM-DAN holds promise as a novel fluorescent ligand to measure the affinity of prospective drugs binding at the NMDAR PCP-site and may circumvent the use of radioligands. MDPI 2019-11-13 /pmc/articles/PMC6891720/ /pubmed/31766120 http://dx.doi.org/10.3390/molecules24224092 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ndzibongwana, Sethu Ngobese, Samukelo Sayed, Ahmad Shongwe, Ciniso White-Phillips, Simon Joubert, Jacques Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title | Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title_full | Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title_fullStr | Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title_full_unstemmed | Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title_short | Structural Analysis, Molecular Modelling and Preliminary Competition Binding Studies of AM-DAN as a NMDA Receptor PCP-Site Fluorescent Ligand |
title_sort | structural analysis, molecular modelling and preliminary competition binding studies of am-dan as a nmda receptor pcp-site fluorescent ligand |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891720/ https://www.ncbi.nlm.nih.gov/pubmed/31766120 http://dx.doi.org/10.3390/molecules24224092 |
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