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Rational Design of ¿-Conotoxin RegIIA Analogues Selectively Inhibiting the Human ¿3ß2 Nicotinic Acetylcholine Receptor through Computational Scanning

Journal Article


Abstract


  • Engineering the selectivity of α-conotoxins for nicotinic acetylcholine receptors (nAChRs) presents considerable complexity and challenges, as it involves the optimization of their binding affinities to multiple highly conserved nAChR subtypes. Here, we applied a computational-based scanning approach for the rational design of α-conotoxin RegIIA analogues selectively targeting the human (h) α3β2 versus hα3β4 nAChRs. Binding mode analyses suggested that several residues in loop II of RegIIA (position 9, 10, and 11) formed nonconserved interactions with residues of the β2 and β4 subunits. The molecular mechanics generalized Born surface area method was applied for in silico sequence scanning of RegIIA position 9, 10, and 11 on frames extracted from single molecular dynamics simulation trajectory. RegIIA analogues with favorable predicted binding affinities solely to the hα3β2 nAChR were synthesized and tested electrophysiologically. We report three RegIIA analogues, with position 9 aromatic residue substitutions, exhibiting a 10-to 37-fold subtype selectivity improvement for hα3β2 compared to hα3β4 nAChR. The in silico scanning method proposed from this study has considerable potential for the efficient design of nAChR subtype selective antagonists in the future.

Publication Date


  • 2020

Citation


  • Xu, Q., Tae, H. S., Wang, Z., Jiang, T., Adams, D. J., & Yu, R. (2020). Rational Design of ¿-Conotoxin RegIIA Analogues Selectively Inhibiting the Human ¿3ß2 Nicotinic Acetylcholine Receptor through Computational Scanning. ACS Chemical Neuroscience, 11(18), 2804-2811. doi:10.1021/acschemneuro.0c00293

Scopus Eid


  • 2-s2.0-85091127244

Start Page


  • 2804

End Page


  • 2811

Volume


  • 11

Issue


  • 18

Abstract


  • Engineering the selectivity of α-conotoxins for nicotinic acetylcholine receptors (nAChRs) presents considerable complexity and challenges, as it involves the optimization of their binding affinities to multiple highly conserved nAChR subtypes. Here, we applied a computational-based scanning approach for the rational design of α-conotoxin RegIIA analogues selectively targeting the human (h) α3β2 versus hα3β4 nAChRs. Binding mode analyses suggested that several residues in loop II of RegIIA (position 9, 10, and 11) formed nonconserved interactions with residues of the β2 and β4 subunits. The molecular mechanics generalized Born surface area method was applied for in silico sequence scanning of RegIIA position 9, 10, and 11 on frames extracted from single molecular dynamics simulation trajectory. RegIIA analogues with favorable predicted binding affinities solely to the hα3β2 nAChR were synthesized and tested electrophysiologically. We report three RegIIA analogues, with position 9 aromatic residue substitutions, exhibiting a 10-to 37-fold subtype selectivity improvement for hα3β2 compared to hα3β4 nAChR. The in silico scanning method proposed from this study has considerable potential for the efficient design of nAChR subtype selective antagonists in the future.

Publication Date


  • 2020

Citation


  • Xu, Q., Tae, H. S., Wang, Z., Jiang, T., Adams, D. J., & Yu, R. (2020). Rational Design of ¿-Conotoxin RegIIA Analogues Selectively Inhibiting the Human ¿3ß2 Nicotinic Acetylcholine Receptor through Computational Scanning. ACS Chemical Neuroscience, 11(18), 2804-2811. doi:10.1021/acschemneuro.0c00293

Scopus Eid


  • 2-s2.0-85091127244

Start Page


  • 2804

End Page


  • 2811

Volume


  • 11

Issue


  • 18