Login Register Cart 0
Generic placeholder image

Mini-Reviews in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1389-5575
ISSN (Online): 1875-5607

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Three-dimensional Quantitative Structure-activity Relationship (3DQSAR) and Molecular Docking Study of 2-((pyridin-3-yloxy)methyl) Piperazines as α7 Nicotinic Acetylcholine Receptor Modulators for the Treatment of Inflammatory Disorders

Author(s): Deepika Purohit, Vandana Saini, Sanjiv Kumar, Ajit Kumar and Balasubramanian Narasimhan*

Volume 20, Issue 11, 2020

Page: [1031 - 1041] Pages: 11

DOI: 10.2174/1389557519666190904151227

Price: $65

Abstract

Background & Objective: Comparative molecular field analysis (CoMFA) of 27 analogues of 2-((pyridin-3-yloxy)methyl)piperazine derivatives was carried out using software Tripos SYBYL X. Optimal r2 (0.854) and q2 (0.541) values were obtained for the developed 3D-QSAR model. The contour plots obtained from CoMFA analysis have shown 13.84% steric contribution and 66.14% electrostatic contribution towards an anti-inflammatory activity.

Methods: The homology model of the receptor protein, α7 nicotinic acetylcholine, was generated in SWISS MODELLER using auto template mode and was analysed for the quality using Procheck, QMEAN Z-score, Anolea and GROMOS plots. The QMEAN score for the model was observed to be - 3.862. The generated model of alpha 7 nicotinic acetylcholine receptor was used for docking study of 27 piperazine analogues using Auto-Dock 4.2.5.1.

Results: The dock score obtained from docking analysis was then correlated with experimental pIC50 values for in-silico validation of the developed CoMFA model and a good correlation was obtained with correlation coefficient (r2) value of -0.7378.

Conclusion: The present investigation suggests an optimal 3D-QSAR with CoMFA model for further evaluating new chemical entities based on piperazine skeleton.

Keywords: Piperazine derivatives, anti-inflammatory, nicotinic acetylcholine receptors, docking, CoMFA study, 3D-QSAR.

« Previous Next »
Graphical Abstract

[1]
Simbirtsev, A.S.; Kozlov, I.G. Mechanical Stretch and Cytokines; Springer, 2012, Vol. 5, pp. 1-34.
[2]
Ulloa, L.; Tracey, K.J. The “cytokine profile”: a code for sepsis. Trends Mol. Med., 2005, 11(2), 56-63.
[http://dx.doi.org/10.1016/j.molmed.2004.12.007] [PMID: 15694867]
[3]
Martin, G.S.; Mannino, D.M.; Eaton, S.; Moss, M. The epidemiology of sepsis in the United States from 1979 through 2000. N. Engl. J. Med., 2003, 348(16), 1546-1554.
[http://dx.doi.org/10.1056/NEJMoa022139] [PMID: 12700374]
[4]
de Jonge, W.J.; Ulloa, L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br. J. Pharmacol., 2007, 151(7), 915-929.
[http://dx.doi.org/10.1038/sj.bjp.0707264] [PMID: 17502850]
[5]
Wang, H.; Yu, M.; Ochani, M.; Amella, C.A.; Tanovic, M.; Susarla, S.; Li, J.H.; Wang, H.; Yang, H.; Ulloa, L.; Al-Abed, Y.; Czura, C.J.; Tracey, K.J. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature, 2003, 421(6921), 384-388.
[http://dx.doi.org/10.1038/nature01339] [PMID: 12508119]
[6]
Clark, R.B.; Lamppu, D.; Libertine, L.; McDonough, A.; Kumar, A.; LaRosa, G.; Rush, R.; Elbaum, D. Discovery of novel 2-((pyridin-3-yloxy)methyl)piperazines as α7 nicotinic acetylcholine receptor modulators for the treatment of inflammatory disorders. J. Med. Chem., 2014, 57(10), 3966-3983.
[http://dx.doi.org/10.1021/jm5004599] [PMID: 24814197]
[7]
http://www.rcsb.org (Accessed July 8, 2014).
[8]
https://swissmodel.expasy.org
[9]
Benkert, P.; Tosatto, S.C.E.; Schomburg, D. QMEAN: A comprehensive scoring function for model quality assessment. Proteins, 2008, 71(1), 261-277.
[http://dx.doi.org/10.1002/prot.21715] [PMID: 17932912]
[10]
Pal, D.; Chakrabarti, P. On residues in the disallowed region of the Ramachandran map. Biopolymers, 2002, 63(3), 195-206.
[http://dx.doi.org/10.1002/bip.10051] [PMID: 11787007]
[11]
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID: 12612645]
[12]
Verma, J.; Khedkar, V.M.; Coutinho, E.C. 3D-QSAR in drug design--a review. Curr. Top. Med. Chem., 2010, 10(1), 95-115.
[http://dx.doi.org/10.2174/156802610790232260] [PMID: 19929826]
[13]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110(18), 5959-5967.
[http://dx.doi.org/10.1021/ja00226a005] [PMID: 22148765]
[14]
Akula, N.V.M.K.; Kumar, S.; Singh, V.; Tiwari, M. Homology modeling and QSAR analysis of 1,3,4-thiadiazole and 1,3,4-triazole derivatives as carbonic anhydrase inhibitors. Indian J. Biochem. Biophys., 2010, 47(4), 234-242.
[PMID: 21174951]
[15]
Blum, L.C.; van Deursen, R.; Bertrand, S.; Mayer, M.; Bürgi, J.J.; Bertrand, D.; Reymond, J.L. Discovery of α7-nicotinic receptor ligands by virtual screening of the chemical universe database GDB-13. J. Chem. Inf. Model., 2011, 51(12), 3105-3112.
[http://dx.doi.org/10.1021/ci200410u] [PMID: 22077916]

Rights & Permissions Print Cite
Article Metrics
13
3
© 2024 Bentham Science Publishers | Privacy Policy