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Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor

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Abstract

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

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Acknowledgments

We are grateful to Prof. Philip Biggin for his comments about this manuscript. This work was supported by grants from the Natural Science Foundation of China (NSFC) (no. 81502977), the China Postdoctoral Science Foundation (861505020050 and 2016 T90655), and the Special Foundation for Qingdao Basic Research Program (15-9-1-85-jch). The authors gratefully acknowledge the funding from the above sources.

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Authors and Affiliations

  1. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao, 266003, China

    Nargis Tabassum, Qianyun Ma, Guanzhao Wu, Tao Jiang & Rilei Yu

  2. Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266003, China

    Nargis Tabassum, Qianyun Ma, Guanzhao Wu, Tao Jiang & Rilei Yu

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  1. Nargis Tabassum
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  2. Qianyun Ma
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  4. Tao Jiang
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  5. Rilei Yu
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Corresponding author

Correspondence to Rilei Yu.

Electronic supplementary material

Figure S1

The opening distances of the C-loop of AChBP bound to full agonists (“agonists” in the figure), partial agonists, and antagonists of α7 nAChR (data are for the relevant crystal structures). When AChBP is bound to full agonists (PDB ID: 2BYQ, 2WNL), the C loop is more closed than when AChBP is bound to partial agonists (PDB ID: 4AFH, 2WNC, 2WNJ, 2WN9) and antagonists (PDB ID: 2XYS, 2XYT). Overall, the C-loop opening distance increases in the following order: full agonists < partial agonists < antagonists. (DOC 8732 kb).

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Tabassum, N., Ma, Q., Wu, G. et al. Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor. J Mol Model 23, 251 (2017). https://doi.org/10.1007/s00894-017-3419-4

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  • DOI: https://doi.org/10.1007/s00894-017-3419-4

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