Interaction of rat α9α10 nicotinic acetylcholine receptor with α-conotoxin RgIA and Vc1.1: Insights from docking, molecular dynamics and binding free energy contributions

Li, Rui; Li, Xincan; Jiang, J.-P.; Tian, Yuanyuan; Liu, Danrui; Zhangsun, Donting; Fu, Ying; Wu, Yong; Luo, Sulan

doi:10.1016/j.jmgm.2019.06.020

Cited by 2 publications

(1 citation statement)

References 41 publications

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“…Finally, a docking model of analogue 6 to the receptor based on Rosetta protein–protein docking calculations was generated to help inform SAR efforts. We found that key binding interactions revealed by the α-RgIA/α9(+) crystal structure (PDB 6HY7) were predicted by Rosetta to also be present in the case of analogue 6 binding with α9/α10 nAChR . Specifically, analogue 6 residues Asp5 and Arg7 form an intramolecular salt bridge, with the remaining amine on Arg7 hydrogen bonding to the backbone carbonyl of receptor residue Pro200 on both the α9(+) and α10(+) surfaces, an interaction that is nearly identical to the reported crystal structure (Figure A,C).…”

Section: Results and Discussionsupporting

confidence: 73%

Development of Conformationally Constrained α-RgIA Analogues as Stable Peptide Antagonists of Human α9α10 Nicotinic Acetylcholine Receptors

et al. 2020

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Non-opioid therapeutics for the treatment of neuropathic pain are urgently needed to address the ongoing opioid crisis. Peptides from cone snail venoms have served as invaluable molecules to target key pain-related receptors but can suffer from unfavorable physicochemical properties, which limit their therapeutic potential. In this work, we developed conformationally constrained α-RgIA analogues with high potency, receptor selectivity, and enhanced human serum stability to target the human α9α10 nicotinic acetylcholine receptor. The key lactam linkage introduced in α-RgIA fixed the favored globular conformation and suppressed disulfide scrambling. The NMR structure of the macrocyclic peptide overlays well with that of α-RgIA4, demonstrating that the cyclization does not perturb the overall conformation of backbone and key side-chain residues. Finally, a molecular docking model was used to rationalize the selective binding between a macrocyclic analogue and the α9α10 nicotinic acetylcholine receptor. These conformationally constrained antagonists are therefore promising candidates for antinociceptive therapeutic intervention.

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Section: Results and Discussionsupporting

confidence: 73%

Development of Conformationally Constrained α-RgIA Analogues as Stable Peptide Antagonists of Human α9α10 Nicotinic Acetylcholine Receptors

et al. 2020

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N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor

Li,

Zhou,

Tae

et al. 2024

J. Med. Chem.

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α9α10 nicotinic acetylcholine receptors (nAChRs) are a promising nonopioid analgesic target, with α9α10 nAChR antagonists showing efficacy against chemotherapy-induced hyperalgesia and allodynia. GeX-2, a potent analgesic conotoxin antagonist of α9α10 nAChRs, has limited serum stability. This study improved GeX-2 stability by capping its N-terminal with fatty acids or polyethylene glycol chains, which enhanced its serum stability but eliminated activity at G protein-coupled γ-aminobutyric acid type B (GABA B ) receptor-coupled Ca V 2.2 channels while preserving activity at α9α10 nAChRs. In vivo, α9α10 nAChRs antagonism alone did not alleviate neuropathic pain, highlighting the importance of GABA B receptor-coupled Ca V 2.2 channels in GeX-2's antinociceptive effects in the chronic constriction injury rat model. The GeX-2 analogue, with an N-terminal methyl group, showed improved activity and selectivity for α9α10 nAChRs, increased serum half-life, and strong analgesic effects in oxaliplatininduced cold allodynia models. AlphaFold3 and molecular dynamics simulations provided insights into the binding modes and the effects of N-terminal capping, which informed future peptide therapeutic developments.

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Interaction of rat α9α10 nicotinic acetylcholine receptor with α-conotoxin RgIA and Vc1.1: Insights from docking, molecular dynamics and binding free energy contributions

Cited by 2 publications

References 41 publications

Development of Conformationally Constrained α-RgIA Analogues as Stable Peptide Antagonists of Human α9α10 Nicotinic Acetylcholine Receptors

Development of Conformationally Constrained α-RgIA Analogues as Stable Peptide Antagonists of Human α9α10 Nicotinic Acetylcholine Receptors

N-Terminal Capping of the αO-Conotoxin Analogue GeX-2 Improves the Serum Stability and Selectivity toward the Human α9α10 Nicotinic Acetylcholine Receptor

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