Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors

Yanjun Hou; Xuan Zheng; Hongmei Zhong; Feng Chen; Guiyang Yan; Kaicong Cai

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Yanjun Hou, Xuan Zheng, Hongmei Zhong, Feng Chen, Guiyang Yan, Kaicong Cai. Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors[J]. Chinese Journal of Chemical Physics .

Citation:

Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors

a College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou, 350007, P. R. China;
b Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde, 352100, P. R. China;
c Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen, 361005, P. R. China;
d Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Funds:

This work was financially supported by the National Natural Science Foundation of China (21103021), the New Century Excellent Talent Project in University of Fujian Province, Opening Project of PCOSS, Xiamen University (201904).

Received Date: 2020-09-17
Available Online: 2020-11-20

Abstract

The interaction between Amyloid β (Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer's disease. Here, molecular docking and molecular dynamics (MD) simulations were performed for the structural dynamics of the docking complex consists of Aβ and α7-nAChR (α7 nicotinic acetylcholine receptor), and the inter-molecular interactions between ligand and receptor were revealed. The results show that Aβ_25-35 bound to α7-nAChR through hydrogen bonds and complementary shape, and the Aβ_25-35 fragments would easily assemble in the ion channel of α7-nAChR, then block the ion transfer process and induce neuronal apoptosis. The simulated amide-I band of Aβ_25-35 in the complex is located at 1650.5 cm^-1, indicating the backbone of Aβ_25-35 tends to present random coil conformation, which is consistent with the result obtained from cluster analysis. Currently existed drugs were used as templates for virtual screening, eight new drugs were designed and semi-flexible docking was performed for their performance. The results show that, the interactions between new drugs and α7-nAChR are strong enough to inhibit the aggregation of Aβ_25-35 fragments in the ion channel, and also be of great potential in the treatment of Alzheimer's disease.
- Amyloid β peptide,
- Acetylcholine receptor,
- Molecular dynamics simulation,
- Molecular docking,
- Virtual screening

References

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[2]	M. Lorenzi; A. Altmann; B. Gutman et al., Proc. Natl. Acad. Sci. USA 115, 3162 (2018).
[3]	D. D. Chu; F. Liu, Acs Chemical Neuroscience 10, 931 (2019).
[4]	C. M. Dobson, Trends Biochem. Sci. 24, 329 (1999).
[5]	C. M. Dobson, Nature 426, 884 (2003).
[6]	M. Stefani; C. M. Dobson, Journal of Molecular Medicine-Jmm 81, 678 (2003).
[7]	A. S. DeToma; S. Salamekh; A. Ramamoorthy et al., Chem. Soc. Rev. 41, 608 (2012).
[8]	S. Parthasarathy; M. Inoue; Y. Xiao et al., J. Am. Chem. Soc. 137, 6480 (2015).
[9]	A. S.-Y. Law; L. C.-C. Lee; M. C.-L. Yeung et al., J. Am. Chem. Soc. 141, 18570 (2019).
[10]	I. W. Hamley, Angew. Chem.-Int. Edit. 46, 8128 (2007).
[11]	K. Kurbatskaya; E. C. Phillips; C. L. Croft et al., Acta Neuropathol. Commun. 4, 34 (2016).
[12]	C. M. Henstridge; E. Pickett; T. L. Spires-Jones, Ageing Res. Rev. 28, 72 (2016).
[13]	C. Wallin; Y. Hiruma; S. K. T. S. Wärmländer et al., J. Am. Chem. Soc. 140, 8138 (2018).
[14]	N. J. Economou; M. J. Giammona; T. D. Do et al., J. Am. Chem. Soc. 138, 1772 (2016).
[15]	B. Murray; B. Sharma; G. Belfort, Acs Chemical Neuroscience 8, 432 (2017).
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[17]	A. M. D'Ursi; M. R. Armenante; R. Guerrini et al., J. Med. Chem. 47, 4231 (2004).
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[19]	T. Kohno; K. Kobayashi; T. Maeda et al., Biochemistry 35, 16094 (1996).
[20]	M. del Mar Martínez-Senac; J. Villalaín; J. C. Gómez-Fernández, Eur. J. Biochem. 265, 744 (1999).
[21]	Q. S. Liu; H. Kawai; D. K. Berg, Proc. Natl. Acad. Sci. USA 98, 4734 (2001).
[22]	D. Bertrand; J. L. Galzi; A. Devillers-Thiéry et al., Proceedings of the National Academy of Sciences 90, 6971 (1993).
[23]	K. T. Dineley; A. A. Pandya; J. L. Yakel, Trends Pharmacol. Sci. 36, 96 (2015).
[24]	H. Lin; S. Vicini; F. C. Hsu et al., Proc. Natl. Acad. Sci. USA 107, 16661 (2010).
[25]	L. A. Mohamed; H. Qosa; A. Kaddoumi, Acs Chemical Neuroscience 6, 725 (2015).
[26]	M. Criado; J. Mulet; F. Sala et al., Acs Chemical Neuroscience 7, 1157 (2016).
[27]	A. K. Hamouda; T. Kimm; J. B. Cohen, J. Neurosci. 33, 485 (2013).
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[35]	K. Cai; T. Su; S. Lin et al., Spectrochim. Acta, Part A 117, 548 (2014).
[36]	K. Cai; F. Du; X. Zheng et al., J. Phys. Chem. B 120, 1069 (2016).
[37]	K. Cai; X. Zheng; F. Du, Spectrochim. Acta, Part A 183, 150 (2017).
[38]	K. Cai; X. Zheng; J. Liu et al., Spectrochim. Acta, Part A 219, 391 (2019).
[39]	J. K. Carr; A. V. Zabuga; S. Roy et al., J. Chem. Phys. 140, 224111 (2014).
[40]	C.-J. Feng; A. Tokmakoff, J. Chem. Phys. 147, 085101 (2017).
[41]	A. Ghosh; J. S. Ostrander; M. T. Zanni, Chem. Rev. 117, 10726 (2017).
[42]	M. Reppert; A. Tokmakoff, Annu. Rev. Phys. Chem. 67, 359 (2016).
[43]	J. C. Phillips; R. Braun; W. Wang et al., J. Comput. Chem. 26, 1781 (2005).
[44]	A. D. MacKerell, Jr.; D. Bashford; M. Bellott et al., J. Phys. Chem. B 102, 3586 (1998).
[45]	A. D. MacKerell, Jr.; M. Feig; C. L. Brooks, J. Comput. Chem. 25, 1400 (2004).
[46]	W. L. Jorgensen; J. Chandrasekhar; J. D. Madura et al., J. Chem. Phys. 79, 926 (1983).
[47]	B. R. Miller; T. D. McGee; J. M. Swails et al., J. Chem. Theory Comput. 8, 3314 (2012).
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[49]	K. Cai; X. Zheng; Y. Liu et al., Acta Phys. -Chim. Sin. 32, 1289 (2016).
[50]	L. C. Mayne; B. Hudson, J. Phys. Chem. 95, 2962 (1991).
[51]	M. J. Frisch; G. W. Trucks; H. B. Schlegel et al., Gaussian 09, Revision A.01, Gaussian Inc., Wallingford CT., (2009).
[52]	M. H. Jamroz, Spectrochim. Acta, Part A 114, 220 (2013).
[53]	S. Pronk; S. Pall; R. Schulz et al., Bioinformatics 29, 845 (2013).
[54]	W. Humphrey; A. Dalke; K. Schulten, J. Mol. Graphics 14, 33 (1996).

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Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors

a College of Chemistry and Materials Science, Fujian Provincial Key Laboratory of Advanced Materials Oriented Chemical Engineering, Fujian Normal University, Fuzhou, 350007, P. R. China;

b Fujian Provincial Key Laboratory of Featured Biochemical and Chemical Materials, Ningde Normal University, Ningde, 352100, P. R. China;

c Fujian Provincial Key Laboratory of Theoretical and Computational Chemistry, Xiamen, 361005, P. R. China;

d Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

Funds:

Received Date: 2020-09-17

Available Online: 2020-11-20

Key words:

Abstract:

The interaction between Amyloid β (Aβ) peptide and acetylcholine receptor is the key for our understanding of how Aβ fragments block the ion channels within the synapses and thus induce Alzheimer's disease. Here, molecular docking and molecular dynamics (MD) simulations were performed for the structural dynamics of the docking complex consists of Aβ and α7-nAChR (α7 nicotinic acetylcholine receptor), and the inter-molecular interactions between ligand and receptor were revealed. The results show that Aβ_25-35 bound to α7-nAChR through hydrogen bonds and complementary shape, and the Aβ_25-35 fragments would easily assemble in the ion channel of α7-nAChR, then block the ion transfer process and induce neuronal apoptosis. The simulated amide-I band of Aβ_25-35 in the complex is located at 1650.5 cm^-1, indicating the backbone of Aβ_25-35 tends to present random coil conformation, which is consistent with the result obtained from cluster analysis. Currently existed drugs were used as templates for virtual screening, eight new drugs were designed and semi-flexible docking was performed for their performance. The results show that, the interactions between new drugs and α7-nAChR are strong enough to inhibit the aggregation of Aβ_25-35 fragments in the ion channel, and also be of great potential in the treatment of Alzheimer's disease.

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Reference (54)

[1]	X. Zhou; Y. Chen; K. Y. Mok et al., Proc. Natl. Acad. Sci. USA 115, 1697 (2018).
[2]	M. Lorenzi; A. Altmann; B. Gutman et al., Proc. Natl. Acad. Sci. USA 115, 3162 (2018).
[3]	D. D. Chu; F. Liu, Acs Chemical Neuroscience 10, 931 (2019).
[4]	C. M. Dobson, Trends Biochem. Sci. 24, 329 (1999).
[5]	C. M. Dobson, Nature 426, 884 (2003).
[6]	M. Stefani; C. M. Dobson, Journal of Molecular Medicine-Jmm 81, 678 (2003).
[7]	A. S. DeToma; S. Salamekh; A. Ramamoorthy et al., Chem. Soc. Rev. 41, 608 (2012).
[8]	S. Parthasarathy; M. Inoue; Y. Xiao et al., J. Am. Chem. Soc. 137, 6480 (2015).
[9]	A. S.-Y. Law; L. C.-C. Lee; M. C.-L. Yeung et al., J. Am. Chem. Soc. 141, 18570 (2019).
[10]	I. W. Hamley, Angew. Chem.-Int. Edit. 46, 8128 (2007).
[11]	K. Kurbatskaya; E. C. Phillips; C. L. Croft et al., Acta Neuropathol. Commun. 4, 34 (2016).
[12]	C. M. Henstridge; E. Pickett; T. L. Spires-Jones, Ageing Res. Rev. 28, 72 (2016).
[13]	C. Wallin; Y. Hiruma; S. K. T. S. Wärmländer et al., J. Am. Chem. Soc. 140, 8138 (2018).
[14]	N. J. Economou; M. J. Giammona; T. D. Do et al., J. Am. Chem. Soc. 138, 1772 (2016).
[15]	B. Murray; B. Sharma; G. Belfort, Acs Chemical Neuroscience 8, 432 (2017).
[16]	C. J. Pike; A. J. Walencewicz-Wasserman; J. Kosmoski et al., J. Neurochem. 64, 253 (1995).
[17]	A. M. D'Ursi; M. R. Armenante; R. Guerrini et al., J. Med. Chem. 47, 4231 (2004).
[18]	E. Terzi; G. Hoelzemann; J. Seelig, Biochemistry 33, 7434 (1994).
[19]	T. Kohno; K. Kobayashi; T. Maeda et al., Biochemistry 35, 16094 (1996).
[20]	M. del Mar Martínez-Senac; J. Villalaín; J. C. Gómez-Fernández, Eur. J. Biochem. 265, 744 (1999).
[21]	Q. S. Liu; H. Kawai; D. K. Berg, Proc. Natl. Acad. Sci. USA 98, 4734 (2001).
[22]	D. Bertrand; J. L. Galzi; A. Devillers-Thiéry et al., Proceedings of the National Academy of Sciences 90, 6971 (1993).
[23]	K. T. Dineley; A. A. Pandya; J. L. Yakel, Trends Pharmacol. Sci. 36, 96 (2015).
[24]	H. Lin; S. Vicini; F. C. Hsu et al., Proc. Natl. Acad. Sci. USA 107, 16661 (2010).
[25]	L. A. Mohamed; H. Qosa; A. Kaddoumi, Acs Chemical Neuroscience 6, 725 (2015).
[26]	M. Criado; J. Mulet; F. Sala et al., Acs Chemical Neuroscience 7, 1157 (2016).
[27]	A. K. Hamouda; T. Kimm; J. B. Cohen, J. Neurosci. 33, 485 (2013).
[28]	W. Qiang; W.-M. Yau; J.-X. Lu et al., Nature 541, 217 (2017).
[29]	S. D. Moran; M. T. Zanni, J Phys. Chem. L 5, 1984 (2014).
[30]	A. M. Alperstein; J. S. Ostrander; T. O. Zhang et al., Proc. Natl. Acad. Sci. USA 201821534 (2019).
[31]	M. K. Petti; J. P. Lomont; M. Maj et al., J. Phys. Chem. B 122, 1771 (2018).
[32]	M. C. Asplund; M. T. Zanni; R. M. Hochstrasser, Proc. Natl. Acad. Sci. USA 97, 8219 (2000).
[33]	A. Remorino; R. M. Hochstrasser, Acc. Chem. Res. 45, 1896 (2012).
[34]	C. R. Baiz; B. Błasiak; J. Bredenbeck et al., Chem. Rev. 120, 7152 (2020).
[35]	K. Cai; T. Su; S. Lin et al., Spectrochim. Acta, Part A 117, 548 (2014).
[36]	K. Cai; F. Du; X. Zheng et al., J. Phys. Chem. B 120, 1069 (2016).
[37]	K. Cai; X. Zheng; F. Du, Spectrochim. Acta, Part A 183, 150 (2017).
[38]	K. Cai; X. Zheng; J. Liu et al., Spectrochim. Acta, Part A 219, 391 (2019).
[39]	J. K. Carr; A. V. Zabuga; S. Roy et al., J. Chem. Phys. 140, 224111 (2014).
[40]	C.-J. Feng; A. Tokmakoff, J. Chem. Phys. 147, 085101 (2017).
[41]	A. Ghosh; J. S. Ostrander; M. T. Zanni, Chem. Rev. 117, 10726 (2017).
[42]	M. Reppert; A. Tokmakoff, Annu. Rev. Phys. Chem. 67, 359 (2016).
[43]	J. C. Phillips; R. Braun; W. Wang et al., J. Comput. Chem. 26, 1781 (2005).
[44]	A. D. MacKerell, Jr.; D. Bashford; M. Bellott et al., J. Phys. Chem. B 102, 3586 (1998).
[45]	A. D. MacKerell, Jr.; M. Feig; C. L. Brooks, J. Comput. Chem. 25, 1400 (2004).
[46]	W. L. Jorgensen; J. Chandrasekhar; J. D. Madura et al., J. Chem. Phys. 79, 926 (1983).
[47]	B. R. Miller; T. D. McGee; J. M. Swails et al., J. Chem. Theory Comput. 8, 3314 (2012).
[48]	D. A. Case; T. E. Cheatham; T. Darden et al., J. Comput. Chem. 26, 1668 (2005).
[49]	K. Cai; X. Zheng; Y. Liu et al., Acta Phys. -Chim. Sin. 32, 1289 (2016).
[50]	L. C. Mayne; B. Hudson, J. Phys. Chem. 95, 2962 (1991).
[51]	M. J. Frisch; G. W. Trucks; H. B. Schlegel et al., Gaussian 09, Revision A.01, Gaussian Inc., Wallingford CT., (2009).
[52]	M. H. Jamroz, Spectrochim. Acta, Part A 114, 220 (2013).
[53]	S. Pronk; S. Pall; R. Schulz et al., Bioinformatics 29, 845 (2013).
[54]	W. Humphrey; A. Dalke; K. Schulten, J. Mol. Graphics 14, 33 (1996).

Structural Dynamics of Amyloid β Peptide Binding to Acetylcholine Receptor and Virtual Screening for Effective Inhibitors

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