In Silico ADME and QSAR Studies on a Set of Coumarin Derivatives As Acetylcholinesterase Inhibitors Against Alzheimer’s Disease: CoMFA, CoMSIA, Topomer CoMFA, and HQSAR

Uttam    Ashok   More; Sameera       Patel; Vidhi       Rahevar; Malleshappa    Ningappa   Noolvi; Tejraj    M.    Aminabhavi; Shrinivas    D.    Joshi

doi:10.2174/1570180816666190712095907

Abstract

Background: Alzheimer’s disease (AD) is increasingly being recognized as one of the lethal diseases in older people. Acetylcholinesterase (AChE) has proven to be the most promising target in AD, used for designing drugs against AD.

Methods: In silico studies, 2D- or 3D-QSAR like hologram QSAR (HQSAR), Topomer comparative molecular field analysis (Topomer CoMFA), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) methods were used to generate QSAR models for acetylcholinesterase inhibitors.

Results: Acetylcholinesterase inhibitors used for the present study contain a series of 7- hydroxycoumarin derivatives connected by piperidine, piperazine, tacrine, triazole, or benzyl fragments through alkyl or amide spacer training set compounds were used to generate best model with a HQSAR q2 value of 0.916 and r2 value of 0.940; a Topomer CoMFA q2 value of 0.907 and r2 value of 0.959, CoMFA q2 value of 0.880 and r2 value of 0.960; and a CoMSIA q2 value of 0.865 and r2 value of 0.941. In addition, contour plots obtained from QSAR models suggested the significant regions that influenced the AChE inhibitory activity.

Conclusion: In light of these results, this study provides knowledge about the structural requirements for the development of more active acetylcholinesterase inhibitors. In addition, the predicted ADME profile helps us to find CNS active molecules, the obtained prediction compared with well-known AChE inhibitors viz., ensaculin, tacrine, galantamine, rivastigmine, and donepezil. Based on the knowledge obtained from these studies, the hybridization approach is one of the best ways to find lead compounds and these findings can be useful in the treatment of Alzheimer's disease.

Keywords: 7-Hydroxy coumarins, HQSAR, CoMFA, CoMSIA, topomer CoMFA, AChE inhibitors.

« Previous Next »

Graphical Abstract

[1] 
Gao H-M, Hong J-S. Why neurodegenerative 
diseases are progressive: uncontrolled inflammation drives disease 
progression Trends Immunol  2008; 29(8): 357-65.
[http://dx.doi.org/10.1016/j.it.2008.05.002] [PMID: 18599350] 
[2] 
Kril JJ, Halliday GM. 2001; 48: 167-217.
[3] 
S Schneider L. A critical review of 
cholinesterase inhibitors as a treatment modality in Alzheimer’s 
disease. Dialogues Clin Neurosci  2000; 2(2): 111-28.
[PMID: 22033801] 
[4] 
Soreq H, Seidman S. Acetylcholinesterase--new roles for an old actor. Nat Rev Neurosci  2001; 2(4): 294-302.
[http://dx.doi.org/10.1038/35067589] [PMID: 11283752] 
[5] 
Enz A, Floersheim P. Cholinesterase 
Inhibitors: An Overview of their Mechanisms of ActionAlzheimer Disease: 
From Molecular Biology to Theraphy; Becker, RE; Giacobini, E; Barton, 
JM; Brown, M.  Boston, MA 1997; pp. 211-5.
[6] 
Brufani M, Filocamo L. Rational Design of New Acetylcholinesterase Inhibitors. 1997.
[7] 
Radić Z, Reiner E, Taylor P. Role of the 
peripheral anionic site on acetylcholinesterase: inhibition by 
substrates and coumarin derivatives. Mol Pharmacol  1991; 39(1): 98-104.
[PMID: 1987454] 
[8] 
Rao J M, Raju B C, Srinivas P V, et al. 2012.
[9] 
Tong W, Lowis DR, Perkins R, et al. Evaluation
 of quantitative structure-activity relationship methods for large-scale
 prediction of chemicals binding to the estrogen receptor. J Chem Inf 
Comput Sci  1998; 38(4): 669-77.
[http://dx.doi.org/10.1021/ci980008g] [PMID: 9722424] 
[10] 
Glennon RA. Higher-end serotonin receptors: 5-HT(5), 5-HT(6), and 5-HT(7). J Med Chem  2003; 46(14): 2795-812.
[http://dx.doi.org/10.1021/jm030030n] [PMID: 12825922] 
[11] 
Solis FJ, Wets RJ-B. Minimization by Random Search Techniques. Math Oper Res  1981; 6(1): 19-30.
[http://dx.doi.org/10.1287/moor.6.1.19] 
[12] 
Cramer RD, Patterson DE, Bunce JD. Comparative
 molecular field analysis (CoMFA). 1. Effect of shape on binding of 
steroids to carrier proteins. J Am Chem Soc  1988; 110(18): 5959-67.
[http://dx.doi.org/10.1021/ja00226a005] [PMID: 22148765] 
[13] 
Klebe G, Abraham U, Mietzner T. Molecular 
similarity indices in a comparative analysis (CoMSIA) of drug molecules 
to correlate and predict their biological activity. J Med Chem  1994; 
37(24): 4130-46.
[http://dx.doi.org/10.1021/jm00050a010] [PMID: 7990113] 
[14] 
Klebe G. Comparative molecular similarity indices analysis: CoMSIA. Perspect Drug Discov Des  1998; 12(0): 87-104.
[http://dx.doi.org/10.1023/A:1017025803403] 
[15] 
Bush BL, Nachbar RB Jr. Sample-distance 
partial least squares: PLS optimized for many variables, with 
application to CoMFA. J Comput Aided Mol Des  1993; 7(5): 587-619.
[http://dx.doi.org/10.1007/BF00124364] [PMID: 8294948] 
[16] 
Dunn WJ, Wold S, Edlund U, Hellberg S, 
Gasteiger J. Multivariate structure-activity relationships between data 
from a battery of biological tests and an ensemble of structure 
descriptors: The PLS method. Quant. Struct.-. Act Relat  1984; 3(4): 
131-7.
[http://dx.doi.org/10.1002/qsar.19840030402] 
[17] 
Geladi P. Notes on the history and nature of partial least squares (PLS) modelling. J Chemometr  1988; 2(4): 231-46.
[http://dx.doi.org/10.1002/cem.1180020403] 
[18] 
Kubinyi H. 3D QSAR in drug design.  Theory Methods and Applications 1993; pp. 1281-306.
[19] 
Lee JY, Doddareddy MR, Cho YS, et al. Comparative QSAR studies on peptide deformylase inhibitors. J Mol Model  2007; 13(5): 543-58.
[http://dx.doi.org/10.1007/s00894-007-0175-x] [PMID: 17333308] 
[20] 
Cramer RD, Bunce JD, Patterson DE. Frank, I.E.
 Crossvalidation, Bootstrapping, and Partial Least Squares Compared with
 Multiple Regression in Conventional QSAR Studies. Quant. Struct.-. Act 
Relat  1988; 7(1): 18-25.
[http://dx.doi.org/10.1002/qsar.19880070105] 
[21] 
Wold S. Cross-Validatory Estimation of the 
Number of Components in Factor and Principal Components Models. 
Technometrics  1978; 20(4): 397-405.
[http://dx.doi.org/10.1080/00401706.1978.10489693] 
[22] 
Alipour M, Khoobi M, Moradi A, et al. Synthesis and anti-cholinesterase activity of new 7-hydroxycoumarin derivatives. Eur J Med Chem  2014; 82: 536-44.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.056] [PMID: 24941128] 
[23] 
Jalili-Baleh L, Forootanfar H, Küçükkılınç TT, et al. Design,
 synthesis and evaluation of novel multi-target-directed ligands for 
treatment of Alzheimer’s disease based on coumarin and lipoic acid 
scaffolds. Eur J Med Chem  2018; 152: 600-14.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.058] [PMID: 29763808] 
[24] 
Moradi A, Faraji L, Nadri H, et al. Synthesis,
 docking study, and biological evaluation of novel umbellipherone/ 
hymecromone derivatives as acetylcholinesterase/butyrylchol-inesterase 
inhibitors. Med Chem Res  2018; 27(7): 1741-7.
[http://dx.doi.org/10.1007/s00044-018-2187-8] 
[25] 
Xie S-S, Wang X-B, Li J-Y, Yang L, Kong L-Y. 
Design, synthesis and evaluation of novel tacrine-coumarin hybrids as 
multifunctional cholinesterase inhibitors against Alzheimer’s disease. 
Eur J Med Chem  2013; 64: 540-53.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.051] [PMID: 23685572] 
[26] 
Clark M, Cramer RD, Van Opdenbosch N. 
Validation of the general purpose tripos 5.2 force field. J Comput Chem 
 1989; 10(8): 982-1012.
[http://dx.doi.org/10.1002/jcc.540100804] 
[27] 
Purcell WP, Singer JA. A brief review and 
table of semiempirical parameters used in the Hueckel molecular orbital 
method. J Chem Eng Data  1967; 12(2): 235-46.
[http://dx.doi.org/10.1021/je60033a020] 
[28] 
Burke TR Jr, Fesen MR, Mazumder A, et al. Hydroxylated aromatic inhibitors of HIV-1 integrase. J Med Chem  1995; 38(21): 4171-8.
[http://dx.doi.org/10.1021/jm00021a006] [PMID: 7473544] 
[29] 
Cramer RD III, Patterson DE, Bunce JD. Recent 
advances in comparative molecular field analysis (CoMFA). Prog Clin Biol
 Res  1989; 291: 161-5.
[PMID: 2726839] 
[30] 
Jilek RJ, Cramer RD. Topomers: a validated 
protocol for their self-consistent generation. J Chem Inf Comput Sci  
2004; 44(4): 1221-7.
[http://dx.doi.org/10.1021/ci049961d] [PMID: 15272829] 
[31] 
QikProp. Schrödinger, LLC New York, NY, USA 2012.
[32] 
Sun Q, Peng D-Y, Yang S-G, Zhu X-L, Yang W-C, 
Yang G-F. Syntheses of coumarin-tacrine hybrids as dual-site 
acetylcholinesterase inhibitors and their activity against 
butylcholinesterase, Aβ aggregation, and β-secretase. Bioorg Med Chem  
2014; 22(17): 4784-91.
[http://dx.doi.org/10.1016/j.bmc.2014.06.057] [PMID: 25088549] 

Rights & Permissions Print Cite

Article Metrics

24

1

Explore Articles

Open Access

Open Access Articles

DOI https://dx.doi.org/10.2174/1570180816666190712095907	Print ISSN 1570-1808
Publisher Name Bentham Science Publisher	Online ISSN 1875-628X

Letters in Drug Design & Discovery

In Silico ADME and QSAR Studies on a Set of Coumarin Derivatives As Acetylcholinesterase Inhibitors Against Alzheimer’s Disease: CoMFA, CoMSIA, Topomer CoMFA, and HQSAR

Abstract

Graphical Abstract

Related Articles