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Exploring the Relationship between Nicotinic Acetylcholine Receptor Ligand Size, Efficiency, Efficacy, and C-Loop Opening

Journal Article


Abstract


  • Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fundamental physiological activities in the nervous system and have become important targets for drug design. For a long time, the acetylcholine binding protein (AChBP) has been used as a surrogate to study the nAChR structure-function. Taking advantage of more than 100 AChBP crystal structures in the Protein DataBank (PDB), we explored the relationship between the size, efficiency, and efficacy of nAChR ligands and the C-loop movement. We found that the size of the ligand is correlated with the opening of the C-loop, which can be used in selecting AChBP crystal structures with appropriate C-loop opening to be used for nAChR ligand docking. Ligand size and C-loop opening are reversely correlated with the ligand efficiency rather than the binding affinity. Ligand efficiency could be accurately predicted using simple computational docking, giving a correlation coefficients (R 2 ) up to 0.73. The efficacy of nAChR ligands might be related to ligand size, C-loop opening, and ligand efficiency. Results from this study are useful for engineering the binding affinity and efficacy of nAChR ligands.

UOW Authors


  •   Ma, Qianyun (external author)
  •   Tae, Han Shen
  •   Wu, Guanzhao (external author)
  •   Jiang, Tao (external author)
  •   Yu, Rilei (external author)

Publication Date


  • 2017

Citation


  • Ma, Q., Tae, H., Wu, G., Jiang, T. & Yu, R. (2017). Exploring the Relationship between Nicotinic Acetylcholine Receptor Ligand Size, Efficiency, Efficacy, and C-Loop Opening. Journal of Chemical Information and Modeling, 57 (8), 1947-1956.

Scopus Eid


  • 2-s2.0-85028526942

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1117

Number Of Pages


  • 9

Start Page


  • 1947

End Page


  • 1956

Volume


  • 57

Issue


  • 8

Place Of Publication


  • United States

Abstract


  • Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fundamental physiological activities in the nervous system and have become important targets for drug design. For a long time, the acetylcholine binding protein (AChBP) has been used as a surrogate to study the nAChR structure-function. Taking advantage of more than 100 AChBP crystal structures in the Protein DataBank (PDB), we explored the relationship between the size, efficiency, and efficacy of nAChR ligands and the C-loop movement. We found that the size of the ligand is correlated with the opening of the C-loop, which can be used in selecting AChBP crystal structures with appropriate C-loop opening to be used for nAChR ligand docking. Ligand size and C-loop opening are reversely correlated with the ligand efficiency rather than the binding affinity. Ligand efficiency could be accurately predicted using simple computational docking, giving a correlation coefficients (R 2 ) up to 0.73. The efficacy of nAChR ligands might be related to ligand size, C-loop opening, and ligand efficiency. Results from this study are useful for engineering the binding affinity and efficacy of nAChR ligands.

UOW Authors


  •   Ma, Qianyun (external author)
  •   Tae, Han Shen
  •   Wu, Guanzhao (external author)
  •   Jiang, Tao (external author)
  •   Yu, Rilei (external author)

Publication Date


  • 2017

Citation


  • Ma, Q., Tae, H., Wu, G., Jiang, T. & Yu, R. (2017). Exploring the Relationship between Nicotinic Acetylcholine Receptor Ligand Size, Efficiency, Efficacy, and C-Loop Opening. Journal of Chemical Information and Modeling, 57 (8), 1947-1956.

Scopus Eid


  • 2-s2.0-85028526942

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1117

Number Of Pages


  • 9

Start Page


  • 1947

End Page


  • 1956

Volume


  • 57

Issue


  • 8

Place Of Publication


  • United States