Interactions of Globular and Ribbon [γ4E]GID with α4β2 Neuronal Nicotinic Acetylcholine Receptor.
FoldX
drug design
molecular dynamics simulation
α-conotoxin
α4β2 nAChR
Journal
Marine drugs
ISSN: 1660-3397
Titre abrégé: Mar Drugs
Pays: Switzerland
ID NLM: 101213729
Informations de publication
Date de publication:
26 Aug 2021
26 Aug 2021
Historique:
received:
15
04
2021
revised:
24
08
2021
accepted:
24
08
2021
entrez:
26
9
2021
pubmed:
27
9
2021
medline:
22
1
2022
Statut:
epublish
Résumé
The α4β2 nAChR is implicated in a range of diseases and disorders including nicotine addiction, epilepsy and Parkinson's and Alzheimer's diseases. Designing α4β2 nAChR selective inhibitors could help define the role of the α4β2 nAChR in such disease states. In this study, we aimed to modify globular and ribbon α-conotoxin GID to selectively target the α4β2 nAChR through competitive inhibition of the α4(+)β2(-) or α4(+)α4(-) interfaces. The binding modes of the globular α-conotoxin [γ4E]GID with rat α3β2, α4β2 and α7 nAChRs were deduced using computational methods and were validated using published experimental data. The binding mode of globular [γ4E]GID at α4β2 nAChR can explain the experimental mutagenesis data, suggesting that it could be used to design GID variants. The predicted mutational energy results showed that globular [γ4E]GID is optimal for binding to α4β2 nAChR and its activity could not likely be further improved through amino-acid substitutions. The binding mode of ribbon GID with the (α4)
Identifiants
pubmed: 34564144
pii: md19090482
doi: 10.3390/md19090482
pmc: PMC8469569
pii:
doi:
Substances chimiques
Conotoxins
0
Nicotinic Antagonists
0
Receptors, Nicotinic
0
nicotinic receptor alpha4beta2
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : ARC Centre of Excellence for Innovations in Peptide and Protein Science
ID : CE200100012
Organisme : Australian Research Council
ID : FL150100146
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