Abstract
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that are involved in fast synaptic transmission and mediated physiological activities in the nervous system. α-Conotoxin ImI exhibits subtype-specific blockade towards homomeric α7 and α9 receptors. In this study, we established a method to build a 2×ImI-dendrimer/h (human) α7 nAChR model, and based on this model, we systematically investigated the molecular interactions between the 2×ImI-dendrimer and hα7 nAChR. Our results suggest that the 2×ImI-dendrimer possessed much stronger potency towards hα7 nAChR than the α-ImI monomer and demonstrated that the linker between α-ImI contributed to the potency of the 2×ImI-dendrimer by forming a stable hydrogen-bond network with hα7 nAChR. Overall, this study provides novel insights into the binding mechanism of α-ImI dendrimer to hα7 nAChR, and the methodology reported here opens an avenue for the design of more selective dendrimers with potential usage as drug/gene carriers, macromolecular drugs, and molecular probes.
Highlights
Nicotinic acetylcholine receptors are cation-selective pentameric ligand-gated ion channels that belong to the Cys-loop receptor family, which includes γ-aminobutyric acid type A (GABAA), glycine, and serotonin (5-HT3) receptors [1,2]
[33], in 3–5% w/w SPL7013 gels, a dendrimer with a polyanionic outer surface was effective in blocking vaginal transmission of simian/HIV-1 virus (SHIV) in macaques [34]
Promising applications, rational design of dendrimeric peptides to achieve optimal bioactivity has proven be challenging is a prerequisite to establish computational method for monomer and α-ImIHence, dimer it possessed similar binding modesa at hα7 Nicotinic acetylcholine receptors (nAChRs)
Summary
Nicotinic acetylcholine receptors (nAChRs) are cation-selective pentameric ligand-gated ion channels that belong to the Cys-loop receptor family, which includes γ-aminobutyric acid type A (GABAA), glycine, and serotonin (5-HT3) receptors [1,2]. Α-Conotoxin ImI (α-ImI) features a short α-helix and two disulfide bonds that link cysteines I–III and II–IV (Figure 1B) It comprises 12 residues and is C-terminal amidated (indicated by * in the sequence) (Figure 1C). Currently,with α-conotoxins are outer receiving increased attention from researchers due to their gels, a dendrimer a polyanionic surface was effective in blocking vaginal transmission of potential medicinal value or potential use as molecular probes for neuropharmacology study. By integrating the a prerequisite to establish a computational method for the design of dendrimeric peptides in silico merits of dendrimers with bioactive peptides, peptide-decorated dendrimers (PDDs) have been prior to chemical synthesis in the laboratory For this purpose, we used a computational modeling extensively fabricated vaccines bound [19–24], antiviral agents and itsantitumor method to build modelstoof generate α-ImI dendrimer with hα nAChR and[25,26], calculated binding therapeutics [27–32]. The α-ImI dimer showed substantially enhanced potency at hα
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