Molecular Modeling Study of Methylxanthines and Tannins as
Β-Secretase Inhibitors

Lenir   Cabral   Correia; Jaderson   Vieira   Ferreira; Carlos   Henrique Tomich   de Paula da Silva; Carlton   Anthony   Taft; Lorane   Izabel   da Silva Hage-Melim

Abstract

Background: Alzheimer’s disease (AD) has been characterized by a progressive loss of cognitive functions, especially memory, impacting the daily life and personality of the elderly. In the present study, we performed molecular modeling of methylxanthines and tannins, with pharmacologic actions as stimulants of the Central Nervous System (CNS) and antioxidant, respectively, present in Paullinia cupana Kunth (guarana), evaluating the theoretical viability of these molecules as an alternative for the treatment of Alzheimer's disease, specifically to act by inhibiting the β-secretase enzyme (BACE-1).

Methods: It has been accomplished optimization of selected chemical structures, derivation of the pharmacophore, docking simulation, as well as prediction of physicochemical, pharmacokinetic (ADME) and toxicological (TOX) properties, ending with the activity prediction and synthetic viability of the selected molecules. For the physicochemical properties, evaluated according to Lipinski’s Rule of Five, only methylxanthines, catechin and epicatechin remained within the parameters evaluated.

Results: In the molecular docking, caffeine, theobromine, theophylline, catechin, epicatechin, and proanthocyanidin, respectively, interacted with 57.14%, 42.86%, 28.57%, 57.14%, 28.57% e 57.14% of the active site amino acid residues of BACE-1. The ADME properties indicated the average permeability of the blood-brain barrier to the molecules caffeine, theobromine, theophylline, catechin and epicatechin, and caffeine, theobromine and theophylline showed high intestinal absorption and low aggregation to plasma proteins. The TOX properties showed only proanthocyanidin as a safer molecule. Only catechin and epicatechin were related to the action of BACE-1 in predicting activity. The synthetic viability of methylxanthine has been evaluated as high, while catechin and epicatechin were median and proanthocyanidin has been evaluated as difficult.

Conclusion: Catechin and epicatechin tannins presented more favorable results indicating the interaction of suppression of the Aβ aggregation, potential BACE-1 inhibitors.

Keywords: Alzheimer's disease, Paullinia cupana, Molecular Docking, BACE-1

Graphical Abstract

[1]
Lennarz, W.J.; Lane, M.D. Eds.; Encyclopedia of Biological Chemistry, 1st ed; Elsevier Inc: Massachusetts, 2004.

[2]
Patrick, G.L. An Introduction to Medicinal Chemistry, 4th ed; Oxford University Press Inc: oxfordshire, 2009.

[3]
Goodman, L.S.; Gilman, A. As bases farmacológicas da terapêutica,  9th ed; Guanabara Koogan: Rio de Janeiro, 2006

[4]
Ferreira, S.; Massano, J. Pharmacological therapy in Alzheimer’s disease: future progress and hopes. Arqui Med.,  2013, 27(2), 65-86.

[5]
Semighini, E.P. Rational planning of beta-secretase inhibitors in Alzheimer’s disease.,  PhD diss., University of São Paulo, 2013

[6]
Trevisan, M.T.S.; Macedo, F.V.V.; Meent, M.; Rhee, I.K.; Verpoorte, R. Seleção de plantas com atividade anticolinas-terase para tratamento da doença de Alzheimer. Quim. Nova,  2003, 26(3), 301-304.
 [http://dx.doi.org/10.1590/S0100-40422003000300002]

[7]
Lidilhone, H.; Genise, V.S.; Neusa, T. Paullinia cupana Kunth (Sapindaceae): A review of its ethnopharmacology, phy-tochemistry and pharmacology. J. Med. Plants Res.,  2013, 7(30), 2221-2229.
 [http://dx.doi.org/10.5897/JMPR2013.5067]

[8]
Braidy, N.; Jugder, B.E.; Poljak, A.; Jayasena, T.; Nabavi, S.M.; Sachdev, P.; Grant, R. Molecular targets of tannic acid in Alzheimer’s disease. Curr. Alzheimer Res.,  2017, 14(8), 861-869.
 [PMID: 28176625]

[9]
Rates, S.M.K. Metilxantinas. In: Pharmacognosy of the Plant; Federal University of Santa Catarina: Porto Alegre, 2011. 

[10]
Antonelli-Ushirobira, T.M.; Yamaguti, E.; Uhemura, L.M.; Palazzo De Mello, J.C. Quality control of samples of Paullin-ia cupana HBK var. sorbilis (Mart.). Ducke. Acta Farm. Bonae,  2004, 23(3), 383-386.

[11]
Otobone, F.J.; Sanches, A.C.; Nagae, R.L.; Martins, J.V.C.; Obici, S.; Mello, J.C.P.; Audi, E.A. Effect of crude extract and its semi purified constituents from guaraná seeds [Paullinia cupana var. sorbilis (Mart.) lucke] on cognitive per-formance in Morris water maze in rats. Braz. Arch. Biol. Technol.,  2005, 48(5), 723-728.
 [http://dx.doi.org/10.1590/S1516-89132005000600007]

[12]
Schneidman-Duhovny, D.; Dror, O.; Inbar, Y.; Nussinov, R.; Wolfson, H.J. PharmaGist: A webserver for ligand-based pharmacophore detection. Nucleic Acids Res.,  2008, 36(Web Server), W223-W228.
 [http://dx.doi.org/10.1093/nar/gkn187] [PMID: 18424800]

[13]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1. Adv. Drug Deliv. Rev.,  2001, 46(1-3), 3-26.
 [http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]

[14]
Goodsell, D.S.; Olson, A.J. Automated docking of substrates to proteins by simulated annealing. Proteins,  1990, 8(3), 195-202.
 [http://dx.doi.org/10.1002/prot.340080302] [PMID: 2281083]

[15]
Yamashita, F.; Hashida, M. In silico approaches for predicting ADME properties of drugs. Drug Metab. Pharmacokinet.,  2004, 19(5), 327-338.
 [http://dx.doi.org/10.2133/dmpk.19.327] [PMID: 15548844]

[16]
Filimonov, D.A.; Poroikov, V.V. Bioactive compound design: Possibilities for industrial use, 1st ed; BIOS Scientific Publishers: Oxford, 1996. 

[17]
Boda, K.; Seidel, T.; Gasteiger, J. Structure and reaction based evaluation of synthetic accessibility. J. Comput. Aided Mol. Des.,  2007, 21(6), 311-325.
 [http://dx.doi.org/10.1007/s10822-006-9099-2] [PMID: 17294248]

[18]
Pinhiero, A.; Silva, K.; Silva, A.; Braga, F.; Silva, C.; Santos, C.; Hage-Melim, L. In silico identification of novel poten-tial BACE-1 inhibitors for Alzheimer’s disease treatment: Molecular docking, pharmacophore modeling and activity and synthetic accessibility predictions. Br. J. Pharm. Res.,  2015, 7(3), 217-229.
 [http://dx.doi.org/10.9734/BJPR/2015/18013]

[19]
Abreu, P.A. Receptor NMDA: Modelagem molecular por homologia e análise SAR de antagonistas de um potencial alvo terapêutico em doenças neurodegenerativas., Dissertação (mestrado). Universidade Federal Fluminense, 2008.

[20]
Passami, F. Modelagem molecular e avaliação da estrutura-atividade acoplados a estudos farmacocinéticos e toxicológicos in silico de derivados heterocíclicos com atividade antiviral., Universidade Federal do Rio de Janeiro, 2009.

[21]
Cole, J.C.; Murray, C.W.; Nissink, J.W.M.; Taylor, R.D.; Taylor, R. Comparing protein-ligand docking programs is diffi-cult. Proteins,  2005, 60(3), 325-332.
 [http://dx.doi.org/10.1002/prot.20497] [PMID: 15937897]

[22]
Zou, Y.; Li, L.; Chen, W.; Chen, T.; Ma, L.; Wang, X.; Xiong, B.; Xu, Y.; Shen, J. Virtual screening and structure-based discovery of indole acylguanidines as potent β-secretase (BACE1) inhibitors. Molecules,  2013, 18(5), 5706-5722.
 [http://dx.doi.org/10.3390/molecules18055706] [PMID: 23681056]

[23]
Xu, Y.; Li, M.; Greenblatt, H.; Chen, W.; Paz, A.; Dym, O.; Peleg, Y.; Chen, T.; Shen, X.; He, J.; Jiang, H.; Silman, I.; Sussman, J.L. Flexibility of the flap in the active site of BACE1 as revealed by crystal structures and molecular dynam-ics simulations. Acta Crystallogr. D Biol. Crystallogr.,  2012, 68(1), 13-25.
 [http://dx.doi.org/10.1107/S0907444911047251] [PMID: 22194329]

[24]
Tettay, C.A.G. Modeling of ligand-residue interactions of hydroxyethylamines that act as inhibitors of the enzyme bace1: A DFT study; University of Cartagena: Colombia, 2011. 

[25]
Barreiro, E.J.; Fraga, C.A.M. Medicinal Chemistry: The basics molecules of drug action; Artmed: Porto Alegre, 2008. 

[26]
Santos, S.C.; Mello, J.C.P. Tannins. In: Pharmacognosy: The Plant to Medicine; University of Santa Cantarina: Porto Alegre, 2011. 

[27]
Ames, B.N.; Gurney, E.G.; Miller, J.A.; Bartsch, H. Carcinogens as frameshift mutagens: Metabolites and derivatives of 2-acetylaminofluorene and other aromatic amine carcinogens. Proc. Natl. Acad. Sci. USA,  1972, 69(11), 3128-3132. [a]
 [http://dx.doi.org/10.1073/pnas.69.11.3128] [PMID: 4564203]

[28]
Pohanka, M. The perspective of caffeine and caffeine derived compounds in therapy. Bratisl. Med. J.,  2015, 116(9), 520-530.
 [http://dx.doi.org/10.4149/BLL_2015_106] [PMID: 26435014]

[29]
Toda, T.; Sunagawa, T.; Kanda, T.; Tagashira, M.; Shirasawa, T.; Shimizu, T. Apple procyanidins suppress amyloid β-protein aggregation. Int. J. Biochem. Res., 2011.

[30]
Arendash, G.W.; Schleif, W.; Rezai-Zadeh, K.; Jackson, E.K.; Zacharia, L.C.; Cracchiolo, J.R.; Shippy, D.; Tan, J. Caf-feine protects Alzheimer’s mice against cognitive impairment and reduces brain β-amyloid production. Neuroscience,  2006, 142(4), 941-952.
 [http://dx.doi.org/10.1016/j.neuroscience.2006.07.021] [PMID: 16938404]

[31]
Cao, C.; Cirrito, J.R.; Lin, X.; Wang, L.; Verges, D.K.; Dickson, A.; Mamcarz, M.; Zhang, C.; Mori, T.; Arendash, G.W.; Holtzman, D.M.; Potter, H. Caffeine suppresses amyloid-β levels in plasma and brain of Alzheimer’s disease transgenic mice. J. Alzheimers Dis.,  2009, 17(3), 681-697.
 [http://dx.doi.org/10.3233/JAD-2009-1071] [PMID: 19581723]

[32]
Fernández-Fernández, L.; Esteban, G.; Giralt, M.; Valente, T.; Bolea, I.; Solé, M.; Sun, P.; Benítez, S.; Morelló, J.R.; Reguant, J.; Ramírez, B.; Hidalgo, J.; Unzeta, M. Catecholaminergic and cholinergic systems of mouse brain are modu-lated by LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids. Food Funct.,  2015, 6(4), 1251-1260.
 [http://dx.doi.org/10.1039/C5FO00052A] [PMID: 25756794]

[33]
SYLVIA. Estimation of the synthetic accessibility of organic compounds. Version 1.4 Program manual and description. Available from: SYLVIA program manual - Molecular Networks GmbH (paperzz.com). 

[34]
Correia, C.R.D.; Oliveira, C.C. The evolution of synthetic organic chemistry. Quo vadis? Sci. Cult.,  2011, 63(1), 33-36.
 [http://dx.doi.org/10.21800/S0009-67252011000100013]

Cite As

Current Physical Chemistry

Molecular Modeling Study of Methylxanthines and Tannins as Β-Secretase Inhibitors

Abstract

Graphical Abstract