The potency of bioactive constituents in Piper betle L. for Alzheimer Targeting on Caspase-3: in silico studies

Anindya Calista Nabila Putri; Raissa Rerey Ashriany; Sitti Kesya Salsabila; Naila Dwi Rahmaharva; Fajar Oktavian Muljono; Firghi Muhammad Fardhan; Dhania Novitasari

doi:10.70392/rw708r52

Authors

Anindya Calista Nabila Putri Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Raissa Rerey Ashriany Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Sitti Kesya Salsabila Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Naila Dwi Rahmaharva Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Fajar Oktavian Muljono Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Firghi Muhammad Fardhan Bachelor Program in Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran Author
Dhania Novitasari Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang Author

DOI:

https://doi.org/10.70392/rw708r52

Keywords:

Alzheimer's disease, Arecoline, Betel Leaves, caspase-3, Molecular docking

Abstract

Alzheimer’s disease (AD) is a neurodegenerative condition that can disrupt memory, cognition, and neurological functions, Recent studies highlight caspase-3 as a potential target, with several lines of evidence pointing to the enzyme's possible role in the onset of AD. Several findings revealed that betel leaf was also examined to treat AD by targeting acetylcholinesterase in vitro and in silico, yet no evaluation had not been done in caspase-3 activity. Using molecular docking, Lipinski's and PreADMET prediction, an in-silico analysis of compounds found in betel leaf (Piper betle L.) was conducted in order to determine whether these compounds could be applied as therapeutic candidates in the treatment of Alzheimer's. To ascertain the drug similarity and ADMET profile of the evaluated ligands, the Mcule and PreADMET sites were used in the studies, which were followed by the molecular docking simulation software AutoDock. The findings demonstrated that all the tested compounds passed the physicochemical features based on Lipinski rule. Further analysis then showed that arecoline bound to the critical amino acid that involved in caspase-3 inhibition. Further evaluation needs to be done to confirm the molecular mechanism of P. betle leaves to AD.

References

Christensen, A., Pike, C.J. APOE genotype affect metabolic and alzheimer-related outcomes induced by Western diet in female EFAD mice. The FASEB Journal 2019, 33(3), 4054-4066.

Aguila, J.L.D., Koboldt, D.C., Black, K., Chasse, R., Norton, J., Wilson, R.K., Cruchaga, C. Alzheimer’s disease: Rare variants with large effect sizes. Current Opinion in Genetics and Development 2015, 33(1), 49-55.

Thakur, A.J., Kamboj, P., Goswami, K., Ahuja, K. Pathophysiology and management of alzheimer’s disease: an overview. Journal of Analytical & Pharmaceutical Research 2018, 7(2), 226-235.

Reardon, S. Alzheimer antibody drugs show questionable potential. Nature Reviews Drug Discovery 2015, 14(9), 591-592.

D’Amelio, M., Sheng, M., Cecconi, F. Caspase-3 in the central nervous system: beyond apoptosis. Trends in Neurosciences 2012, 35(11), 700-709.

Louneva, N., Cohen, J., Hang, L.-Y., Talbot, L., Wilson, R.S, Benett, D.A., Trojanowski, J.Q., Arnold, S.E. Caspase3 is enriched in postsynaptic densities and increased in Alzheimer's disease, The American Journal Pathology 2008, 173(5), 1488-1495.

D'Amelio, M., Cavallucci, V., Middei, S., Marchetti, C., Pacioni, S., Ferri, A., Diamantini, A., De Zio, D., Carrara, P., Battistini, L., Moreno, S., Bacci, A., Ammassari-Teule, M., Marie, H., Cecconi, F. Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease. Nature Neuroscience 2011, 14(1), 69-76.

Stadelmann, C., Deckwerth, T.L., Srinivasan, A., Bancher, C., Bruck, W. Jellinger, K., Lassmann, H. Activation of caspase-3 in single neurons and autophagic granules of granulovacuolar degeneration in Alzheimer's disease. Evidence for apoptotic cell death, The American Journal of Pathololgy 1999, 155(5), 1459-1466.

Unsain, N., Barker, P.A. New views on the misconstrued: executioner caspases and their diverse non-apoptotic roles. Neuron 2015, 88(3), 461-474.

McIlwain, D.R., Berger, T., Mak, T.W. Caspase functions in cell death and disease. Cold Spring Harb Perspect. Biol 2015, 7(4), 1-28.

Mohanto, S., Datta, S., Mandal, S. Piper Betel Linn: A brief study. International Journal of Current Medical and Pharma-ceutical Research 2017, 3(2), 1290-1296

Patil, R.S., Harale, P.M., Shivangekar, K.V., Kumbhar, P.P., Desai, R.R. Phytochemical potential and in vitro antimicrobial activity of Piper betle Linn. leaf extracts. Journal of Chemical and Pharmaceutical Research 2015, 7(5), 1095-1101.

Biswas, P., Anand, U., Saha, S.C., Kant, N., Mishra, T., Masih, H., Bar, A., Pandey, D.K., Jha, N.K., Majumder, M., Das, N., Gadekar, V.S., Shekhawat, M.S., Kumar, N., Kumar, M., Radha, Prockow, J., de la Lastra, J.M.P., Dey, A. Betelvine (Piper betle L.): A comprehensive insight into its ethnopharmacology, phytochemistry, and pharmacological, biomedical and therapeutic attributes. Journal of Cellular and Molecular Medicine 2022, 26(11):3083-3119.

Thamaraikani, I., Kulandhaivel, M. Purification of hydroxychavicol from Piper betle Linn and evaluation of antimicrobial activity against some food paoison causing bacteria. Journal of Pure and Applied Microbiology 2017, 11(4), 1883-1889.

Boontha, S., Taowkaen, J., Phakwan, T., Worauaicha, T., Kamonnate, P., Buranrat, B., Pitaksuteepong, T. Evaluation of an-tioxidant and anticancer effects of Piper betle L (Piperaceae) leaf extract on MCF-7 cells, and preparation of transdermal patches of the extract. Tropical Journal of Pharmaceutical Research 2019, 18(6), 1265-1272.

Das, S., De, B. Acetylcholinesterase inhibitory property of Piper betle leaves. Pharmacologyonline 2011, 1, 700-704.

Debnath, M., Das, S., Bhowmick, S., Karak, S., Saha, A., De, B. Anti-alzheimer’s potential of different varieties of Piper betle leaves and molecular docking analyses of metabolites. Free Radicals and Antioxidants 2021, 11(1), 13-18.

Vara, P.S., Srinivasa, P.B., Himaja, V., Bhagawathi, V., Prasannanjaneyulu, P., Venkteswara, Y.R., Narendra, K.Y. Effect of aqueous Piper betle leaf extract against scopol-amine induced amnesia on albino rats. Journal of Chemical and Pharma-ceutical Sciences 2017, 10, 116-120.

Ahmad, K., Balaramnavar, V.M., Baig, M.H., Srivastava, A.K., Khan, S., Kamal, M.A. Identification of potent caspase-3 in-hibitors for treatment of multi-neurodegenerative diseases using pharmacophore modeling and docking approaches. CNS Neurol Disord Drug Targets 2014, 13(8), 1346-1353.

Xu, Z., Adilijiang, A., Wang, W., You, P., Lin, D., Li, X., He, J. Arecoline attenuates memory impairment and demyelination in a cuprizone-induced mouse model of schizophrenia. Neuroreport 2019, 30(2), 134-138.

Tariot, P.N., Cohen, R.M., Welkowitz, J.A., Sunderland, T., Newhouse, P.A., Murphy, D.L., Weingartner, H. Multiple-dose arecoline infusions in Alzheimer's disease. Arch Gen Psychiatry 1988, 45(10), 901-905.

Az-Zahra, F., Afidika, J., Diamantha, S.D., Rahmani, A.E., Fatimah, S., Aulifa, D.L., Elaine, A.A., Sitinjak, B.D. In silico study of Betel leaves compound (Piper betle L.) as acetylcholinesterase (AChE) enzyme inhibitor in alzheimer disease. vol 2022, 2, 44-58.