The potential of 12 flavonoid compounds as alzheimer's inhibitors through an in silico approach

Gondokesumo, Marisca Evalina; Muslikh, Faisal Akhmal; Pratama, Rizki Rahmadi; Ma’arif, Burhan; Aryantini, Dyah; Alrayan, Reza; Luthfiana, Dewi

doi:10.48309/ecc.2023.419701.1702

Articles in Press

Document Type : Original Research Article

Authors

¹ Faculty of Pharmacy, University of Surabaya, Surabaya, Indonesia

² Faculty of Pharmacy, Bhakti Wiyata Health Sciences Institute, Kediri, Indonesia

³ Faculty of Pharmacy, Islamic University of Kalimantan Muhammad Arsyad Al Banjari Banjarmasin, South Kalimantan, Indonesia

⁴ Department of Pharmacy, Faculty of Medical and Health of Science, Islamic State University Maulana Malik Ibrahim, Malang, Indonesia

⁵ Research and Education Center for Bioinformatics, Indonesia Institute of Bioinformatics, Malang, Indonesia

10.48309/ecc.2023.419701.1702

Abstract

Neurodegenerative disorders (NDD) are age-related condition characterized by a progressive decline in brain functions. This condition has influenced more than 8% of the adult population worldwide, predominately with Alzheimer's disease (AD). Currently, NDD treatment is addressed to relieve existing symptoms, so the effective medication is urgently needed. Flavonoids offer remarkable pharmacological properties applicable to be neuroprotective agents. This study aimed to determine the activity of flavonoid compounds against AD by inhibiting acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) receptors. The method utilized molecular docking studies with the AutoDockTools 4.2.6 program. Analysis of pharmacochemical properties were carried out using SwissADME, while pharmacokinetics and toxicity were examined in the pkCSM web server. The results indicated that α-amyrin and pinoresinol were the most potential AChE and MAO-B inhibitor, respectively. The compounds have lower energy binding values, inhibition constants, and high percentage of similarity with amino acid residues in the ligand native. Analysis of the physicochemical and pharmacokinetic properties showed that these two compounds are acceptable to the body and provides no toxicity. This study demonstrated that the compounds α-amyrin and pinoresinol might potential to be therapeutic agent which primarily act to inhibit AChE and MAO-B in AD progression.

Graphical Abstract

Keywords

Main Subjects

Pharmaceutical Chemistry

References

[1] B.N. Dugger, D.W. Dickson, Pathology of neurodegenerative diseases, Cold Spring Harb. Perspect. Biol., 2017, 9, a028035. [Crossref], [Google Scholar], [Publisher]‎

[2] S. Przedborski S, The two-century journey of Parkinson disease research, Nat. Rev. Neurosci., 2017, 18, 251-259. [Crossref], [Google Scholar], [Publisher]‎

[3] P. Alov, H. Stoimenov, I. Lessigiarska, T. Pencheva, N.T. Tzvetkov, I. Pajeva, I. Tsakovska, In silico identification of multi-target ligands as promising hit compounds for neurodegenerative diseases drug development, Int. J. Mol. Sci., 2022, 23, 13650. [Crossref], [Google Scholar], [Publisher]‎

[4] Z. Han, R. Tian, P. Ren, W. Zhou, P. Wang, M. Luo, S. Jin, Q. Jiang, Parkinson’s disease and Alzheimer’s disease: a Mendelian randomization study, BMC Med. Genet., 2018, 19, 1-9. [Crossref], [Google Scholar], [Publisher]‎

[5] A.A.T. Monfared, M.J. Byrnes, L.A. White, Q. Zhang, Alzheimer’s disease: epidemiology and clinical progression, Neurol. Ther., 2022, 11, 553-569. [Crossref], [Google Scholar], [Publisher]‎

[6] T. Pardo-Moreno, V. García-Morales, S. Suleiman-Martos, A. Rivas-Domínguez, H, Mohamed-Mohamed, J.J. Ramos-Rodríguez, L. Melguizo-Rodríguez, A. González-Acedo, Current treatments and new, tentative therapies for Parkinson’s disease, Pharmaceutics, 2023, 15, 770. [Crossref], [Google Scholar], [Publisher]‎

[7] N.T. Tzvetkov, A.G. Atanasov, Natural product-based multitargeted ligands for Alzheimer's disease treatment?, Future Med. Chem., 2018, 10, 1745-1748 [Crossref], [Google Scholar], [Publisher]‎

[8] S. Ruangritchankul, P. Chantharit, S. Srisuma, L.C. Gray, Adverse drug reactions of acetylcholinesterase inhibitors in older people living with dementia: A comprehensive literature review, Ther. Clin. Risk. Manag., 2021, 927-949. [Crossref], [Google Scholar], [Publisher]‎

[9] S. Schedin-Weiss, M. Inoue, L. Hromadkova, Y. Teranishi, N.G. Yamamoto, B. Wiehager, N. Bogdanovic, B. Winblad, A. Sandebring-Matton, S. Frykman, L.O. Tjernberg, Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels, Alzheimer's Res. Ther., 2017, 9, 1-19. [Crossref], [Google Scholar], [Publisher]‎

[10] T.S. Laban, A. Saadabadi, Monoamine oxidase inhibitors (MAOI), In StatPearls [Internet], StatPearls Publishing, 2022 [Google Scholar], [Publisher]‎

[11] C. Gnanaraj, M. Sekar, S. Fuloria, S.S. Swain, S.H. Gan, K. Chidambaram, N.N.I.M. Rani, T. Balan, S. Stephenie, P.T. Lum, S. Jeyabalan, M.Y. Begum, V. Chandramohan, L. Thangavelu, V. Subramaniyan, N.K. Fuloria, In silico molecular docking analysis of karanjin against alzheimer’s and parkinson’s diseases as a potential natural lead molecule for new drug design, development and therapy, Molecules, 2022, 27, 2834. [Crossref], [Google Scholar], [Publisher]‎

[12] A. Ekalu, J.D. Habila, Flavonoids: isolation, characterization, and health benefits, Beni-Suef Univ. J. Basic Appl. Sci., 2020, 9, 1-14. [Crossref], [Google Scholar], [Publisher]‎

[13] A.R. Tukur, J.D. Habila, R.G-O. Ayo, O.R.A. Lyun, Synthesis, reactions and pharmacological applications of chalcones and their derivatives-a mini review, J. Chem. Rev., 2022, 4, 100-119. [Crossref], [Google Scholar], [Publisher]‎

[14] F.I. Ahmadi, R. Fathollahi, D. Dastan, Phytochemical constituents and biological properties of Scutellaria condensata subsp. Pycnotricha, Iran. Chem. Commun.. 2020, 8, 201-211. [Google Scholar], [Publisher]‎

[15] A.J. Uttu, M.S. Sallau, O.R.A. Iyun, H. Ibrahim, Antimicrobial efficacy of selected strychnos species: a mini review, J. Chem. Rev., 2022, 4, 59-62. [Crossref], [Google Scholar], [Publisher]‎

[16] P. Riwanti, M.S. Arifin, F.A. Muslikh, D. Amalia, I. Abada, A.P. Aditama, B. Ma’arif, Effect of chrysophyllum cainito L. leaves on bone formation in vivo and in silico, Trop. J. Nat. Prod. Res., 2021, 5, 260-264. [Crossref], [Google Scholar], [Publisher]‎

[17] F.A. Muslikh, R.R. Samudra, B. Ma’arif, Z.S. Ulhaq, S. Hardjono, M. Agil, In silico molecular docking and ADMET analysis for drug development of phytoestrogens compound with its evaluation of neurodegenerative diseases, Borneo J. Pharm., 2022, 5, 357-366. [Crossref], [Google Scholar], [Publisher]‎

[18] F.A. Muslikh, R.R. Pratama, M.E. Gondokesumo, Senyawa fitoestrogen untuk potensi terapi penyakit neurodegeneratif terhadap reseptor TLR2: pendekatan in silico, J. Kesehat. Nas., 2023, 12, 17-24. [Crossref], [Google Scholar], [Publisher]‎

[19] B. Ma'arif, F.A. Muslikh, W. Anggraini, M.M. Taek, H. Laswati, M. Agil, In vitro anti-neuroinflammatory effect of genistein (4', 5, 7-trihydroxyisoflavone) on microglia HMC3 cell line, and in silico evaluation of its interaction with estrogen receptor-β, Int. J. Appl. Pharm., 2021, 13, 183-187. [Crossref], [Google Scholar], [Publisher]‎

[20] B. Ma'arif, D.A.P. Fihuda, F.A. Muslikh, S. Syarifuddin, B. Fauziyah, D.P. Sari, M. Agil,Studi in silico penghambatan aktivasi TLR2 ekstrak etanol daun semanggi (Marsilea crenata Presl.), Jurnal Tumbuhan Obat Indonesia, 2022, 15, 31-40. [Crossref], [Google Scholar], [Publisher]‎

[21] G. Sliwoski, S. Kothiwale, J. Meiler, E.W. Lowe, Computational methods in drug discovery, Pharmacol. Rev., 2014, 66, 334-395. [Crossref], [Google Scholar], [Publisher]‎

[22] F.A. Muslikh, R.R. Samudra, B. Ma'arif, Prediksi Senyawa Fraksi Etil Asetat Daun Semanggi (Marsilea crenata Presl.) Sebagai Agen Antineuroinflamasi (agonis ERα), JIKSN: Jurnal Ilmu Kesehatan dan Sains Nusantara, 2023, 1, 10-21. [Google Scholar], [Publisher]‎

[23] B. Ma'arif, M. Aminullah, N.L. Saidah, F.A. Muslikh, A. Rahmawati, Y.Y.A. Indrawijaya, Y.A. Yen, D.P. Sari, M.M. Sari, Prediction of antiosteoporosis activity of thirty-nine phytoestrogen compounds in estrogen receptor-dependent manner through in silico approach, Trop. J. Nat. Prod. Res., 2021, 5, 1727-1734. [Crossref], [Google Scholar], [Publisher]‎

[24] R.R Pratama, Andika, S. Nashihah, Studi penambatan molekuler senyawa flavonoid daun jambu biji (Psidium guajava L.) terhadap Sars-Cov-2 3cl Protease, Medical Sains: Jurnal Ilmiah Kefarmasian, 2021, 6, 9-24. [Crossref], [Google Scholar], [Publisher]‎

[25] B. Ma’arif, F.A. Muslikh, L.A. Najib, R.R.D. Atmaja, M.R. Dianti, In silico antiosteoporosis activity of 96% ethanol extract of chrysophyllum cainito L. leaves, In Proceedings of International Pharmacy Ulul Albab Conference and Seminar (PLANAR), 2021, 1, 61-66). [Crossref], [Google Scholar], [Publisher]‎

[26] C.S. Odoemelam, E. Hunter, J. Simms, Z. Ahmad, M.W. Chang, B. Percival, I.H. Williams, M. Molinari, S.C.L. Kamerlin, P.B. Wilson, In silico ligand docking approaches to characterise the binding of known allosteric modulators to the glucagon-like peptide 1 receptor and prediction of ADME/Tox properties, Appl. Biosci., 2022, 1, 143-162. [Crossref], [Google Scholar], [Publisher]‎

[27] E. Lukitaningsih, A. Wisnusaputra, B.A. Sudarmanto, Scrining in silico active compound of Pachyrrhizus erosus as antitirosinase on Aspergillus oryzae (computattional study with homology modeling and molecular docking), Majalah Obat Tradisional, 2009, 20, 7-15. [Crossref], [Google Scholar], [Publisher]‎

[28] F. Az-Zahra, J. Afidika, S.D. Diamantha, A.E. Rahmani, S. Fatimah, D.L. Aulifa, B.D. Sitinjak, Studi in silico senyawa dalam daun sirih (Piper betle L.) sebagai inhibitor enzim asetilkolinesterase (AChE) pada Penyakit Alzheimer, Indones. J. Pharm., 2022, 2, 44-58. [Crossref], [Google Scholar], [Publisher]‎

[29] F.A. Muslikh, R.R. Pratama, B. Ma'arif, N. Purwitasari, Studi in silico senyawa flavonoid dalam mengambat RNA-dependent RNA polymerase (RdRp) sebagai Antivirus COVID-19, J. Islam. Pharm., 2023, 8, 49-55. [Crossref], [Google Scholar], [Publisher]‎

[30] J.A. Hidayatullah, A.P. Widiyana, D.S. Damayanti, Studi in silico: analisis potensi kacang merah (Phaseolus vulgaris) sebagai anti-Alzheimer dengan aktivasi alfa sekretase dan penghambatan beta secretase, Jurnal Bio Komplementer Medicine, 2022, 9. [Google Scholar], [Publisher]‎

[31] B. Ma'arif, F.A. Muslikh, D. Amalia, A. Mahardiani, L.A Muchlasi, P. Riwanti, M.M. Taek, H.Laswati, M. Agil, Metabolite profiling of the environmental-controlled growth of Marsilea crenata Presl. and its in vitro and In silico antineuroinflammatory properties, Borneo J. Pharm., 2022, 5, 209-228 [Crossref], [Google Scholar], [Publisher]‎

[32] B. Ma’arif, R.R. Samudra, F.A. Muslikh, T.J.D. Dewi, L.A. Muchlasi, Antineuroinflammatory properties of compounds from ethyl acetate fraction of Marsilea crenata C. Presl. against toll-like receptor 2 (3A7B) in silico, In Proceedings of International Pharmacy Ulul Albab Conference and Seminar (PLANAR), 2022, 2, 8-20. [Crossref], [Google Scholar], [Publisher]‎

[33] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Deliv. Rev., 1997, 23, 3-25. [Crossref], [Google Scholar], [Publisher]‎

[34] B. Ma'arif, F.A. Muslikh, D.A.P. Fihuda, S. Syarifuddin, B. Fauziyah, Prediction of compounds from 96% Ethanol Extract of Marsilea crenata Presl. leaves in increasing estrogen receptor-α activation, In Proceedings of International Pharmacy Ulul Albab Conference and Seminar (PLANAR), 2021, 1, 67-76. [Crossref], [Google Scholar], [Publisher]‎

[35] D.E. Pires, T.L. Blundell, D.B. Ascher, pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures, J. Med. Chem., 2015, 58, 4066-4072. [Crossref], [Google Scholar], [Publisher]‎

[36] M.B. Youdim, D. Edmondson, K.F. Tipton, The therapeutic potential of monoamine oxidase inhibitors, Nat. Rev. Neurosci., 2006, 7, 295-309. [Crossref], [Google Scholar], [Publisher]‎

[37] A.C. Tripathi, S. Upadhyay, S. Paliwal, S.K. Saraf, Privileged scaffolds as MAO inhibitors: Retrospect and prospects, Eur. J. Med. Chem., 2018, 145, 445-497. [Crossref], [Google Scholar], [Publisher]‎

[38] T. Behl, D. Kaur, A. Sehgal, S. Singh, N. Sharma, G. Zengin, F.L. Andronie-Cioara, M.M. Toma, S. Bungau, A.G. Bumbu, Role of monoamine oxidase activity in Alzheimer’s disease: an insight into the therapeutic potential of inhibitors, Molecules, 2021, 26, 3724. [Crossref], [Google Scholar], [Publisher]‎

[39] F. Ekström, A. Gottinger, N. Forsgren, M. Catto, L.G. Iacovino, L. Pisani, C. Binda, Dual reversible coumarin inhibitors mutually bound to monoamine oxidase B and acetylcholinesterase crystal structures, ACS Med. Chem. Lett., 2022, 13, 499-506. [Crossref], [Google Scholar], [Publisher]‎

[40] W. Liu, Y. Wang, M.B. Youdim, A novel neuroprotective cholinesterase-monoamine oxidase inhibitor for treatment of dementia and depression in Parkinson’s disease, Ageing Neur. Dis., 2022, 2, [Crossref], [Google Scholar], [Publisher]‎

[41] O.M. Bautista-Aguilera, G. Esteban, M. Chioua, K. Nikolic, D. Agbaba, I. Moraleda, I. Iriepa, E. Soriano, A. Samadi, M. Unzeta, José Marco-Contelles, Multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer’s disease: design, synthesis, biochemical evaluation, ADMET, molecular modeling, and QSAR analysis of novel donepezil-pyridyl hybrids, Drug Des. Devel. Ther., 2014, 1893-1910. [Crossref], [Google Scholar], [Publisher]‎

[42] N. Vaou, E. Stavropoulou, C. Voidarou, Z. Tsakris, G. Rozos, C. Tsigalou, E. Bezirtzoglou, Interactions between medical plant-derived bioactive compounds: Focus on antimicrobial combination effects, Antibiotics, 2022, 11, 1014. [Crossref], [Google Scholar], [Publisher]‎

Eurasian Chemical Communications

The potential of 12 flavonoid compounds as alzheimer's inhibitors through an in silico approach

References

References

Articles in Press, Accepted Manuscript
Available Online from 10 November 2023

The potential of 12 flavonoid compounds as alzheimer's inhibitors through an in silico approach

References

References

Articles in Press, Accepted Manuscript Available Online from 10 November 2023

Articles in Press, Accepted Manuscript
Available Online from 10 November 2023