Study of natural product inhibitors of AChE and their potential therapeutic value for the cholinergic hypothesis in the development
of Alzheimer's disease Chamal Nuwantha de Silva College of Chemical Sciences, Institute of Chemistry Ceylon, Sri Lanka
The most prevalent cause of dementia in elderly persons is Alzheimer's Disease (AD), which is characterized by a progressive deterioration in cognitive function as a result of brain damage. The cholinergic system anomalies are the most severely affected. As cholinergic deficits could be treated by reversibly inhibiting the acetylcholinesterase (AChE) enzyme, inhibition of AChE has become one of the most promising therapy options for AD. The main goal of this study is to investigate the natural product inhibitors of AChE and their potential therapeutic value for the cholinergic hypothesis in the development of AD using molecular docking approach. The crystal structure of hAChE; PDB entry: 6O4W was used in this study. Ten selected drug candidates including Ginsensoside, Apigenin, Curcumin, Mangiferin, Galantamine, Resveratrol, Rivastigmine, Ribalinine, Caranine, and tazettine were docked in order to determine their binding affinities using Avagadro, pYrX, and Discovery Studio 2019 Client software. The bioavailability of the drugs was assessed by using swissADME web server obtaining bioavailability radar and pharmacokinetics was evaluated using protox web server. Then their recent progress in drug development in relation to their properties was discussed in the study. According to the Binding affinities of the inhibitors Apigenin, Ginsensoside, Curcumin, and Caranine showed the highest potential for inhibitory activity respectively. The re docking results showed that the conformation of the docked ligand sufficiently matches with the original ligand; hence the docking protocol was validated. References 1. Francis, P. T.; Palmer, A. M.; Snape, M.; Wilcock, G. K. The Cholinergic Hypothesis of Alzheimer’s Disease: A Review of Progress. J. Neurol. Neurosurg. Psychiatry 1999, 66 (2), 137–147. https://doi.org/10.1136/jnnp.66.2.137. 2. Hostettmann, K.; Borloz, A.; Urbain, A.; Marston, A. Natural Product Inhibitors of Acetylcholinesterase. Curr. Org. Chem. 2006, 10 (8), 825–847. https://doi.org/10.2174/138527206776894410. 3. Khan, H.; Marie, V. Pohanka. Acetylcholinesterase inhibitors (4) Martorana, A.; Esposito, Z.; Koch, G. Beyond the Cholinergic Hypothesis: Do Current Drugs Work in Alzheimer’s Disease? CNS Neurosci. Ther. 2010, 16 4. 235–245.https://doi.org/10.1111/j.1755-5949.2010.00175.x. 5. Lushchekina, S. V.; Makhaeva, G. F.; Novichkova, D. A.; Zueva, I. V.; Kovaleva, N. V.Supercomputer Modeling of Dual-Site Acetylcholinesterase (AChE) Inhibition. Supercomput. Front. Innov. 2018, 5 (4), 89–97. https://doi.org/10.14529/jsfi180410. 6. Dinuka, S. Screening of Sri Lankan Natural Products against Human Acetylcholinesterase ; an in Silico Approach Screening of Sri Lankan Natural Products against Human Acetylcholinesterase ; an in Silico Approach By Delwakkada Liyanage Senal Dinuka Index Number : 1440. 2017, No. July. https://doi.org/10.13140/RG.2.2.29271.78244. 7. Mukherjee, P. K.; Kumar, V.; Mal, M.; Houghton, P. J. Acetylcholinesterase Inhibitors from Plants. Phytomedicine 2007, 14 (4), 289–300. https://doi.org/10.1016/j.phymed.2007.02.002. 8. Chen, X.; Drew, J.; Berney, W.; Lei, W. Neuroprotective Natural Products for Alzheimer’s Disease. Cells 2021, 10 (6), 1–38. https://doi.org/10.3390/cells10061309.
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