Title: Natural Products based P-glycoprotein Activators for Improved beta-amyloid Clearance in Alzheimer's Disease: An in silico Approach Shinde P, Vidyasagar N, Dhulap S, Dhulap A, Hirwani R Ref: Cent Nerv Syst Agents Med Chem, 16:50, 2015 : PubMed
Alzheimer's disease is an age related disorder and is defined to be progressive, irreversible neurodegenerative disease. The potential targets which are associated with the Alzheimer's disease are cholinesterases, N-methyl-D-aspartate receptor, Beta secretase 1, Pregnane X receptor (PXR) and P-glycoprotein (Pgp). P-glycoprotein is a member of the ATP binding cassette (ABC) transporter family, which is an important integral of the blood-brain, blood-cerebrospinal fluid and the blood-testis barrier. Reports from the literature provide evidences that the up-regulation of the efflux pump is liable for a decrease in beta -amyloid intracellular accumulation and is an important hallmark in Alzheimer's disease (AD). Thus, targeting beta-amyloid clearance by stimulating Pgp could be a useful strategy to prevent Alzheimer's advancement. Currently available drugs provide limited effectiveness and do not assure to cure Alzheimer's disease completely. On the other hand, the current research is now directed towards the development of synthetic or natural based therapeutics which can delay the onset or progression of Alzheimer's disease. Since ancient time medicinal plants such as Withania somnifera, Bacopa monieri, Nerium indicum have been used to prevent neurological disorders including Alzheimer's disease. Till today around 125 Indian medicinal plants have been screened on the basis of ethnopharmacology for their activity against neurological disorders. In this paper, we report bioactives from natural sources which show binding affinity towards the Pgp receptor using ligand based pharmacophore development, virtual screening, molecular docking and molecular dynamics simulation studies for the bioactives possessing acceptable ADME properties. These bioactives can thus be useful to treat Alzheimer's disease.
INTRODUCTION: Alzheimer's disease (AD) has increased at an alarming rate and is now a worldwide health problem. Inhibitors of acetylcholinesterase (AChE) leading to inhibition of acetylcholine breakdown constitute the main therapeutic strategy for AD. Psoralen was investigated as inhibitor of AChE enzyme in an attempt to explore its potential for the management of AD. MATERIALS AND METHODS: Psoralen was isolated from powdered Psoralea corylifolia fruits. AChE enzyme inhibitory activity of different concentrations of psoralen was investigated by use of in vitro enzymatic and molecular docking studies. Further, the enzyme kinetics were studied using Lineweaver-Burk plot. RESULTS: Psoralen was found to inhibit AChE enzyme activity in a concentration-dependent manner. Kinetic studies showed psoralen inhibits AChE in a competitive manner. Molecular docking study revealed that psoralen binds well within the binding site of the enzyme showing interactions such as pi-pi stacking and hydrogen bonding with residues present therein. CONCLUSION: The result of AChE enzyme inhibitory activity of the psoralen in this study is promising. It could be further explored as a potential candidate for further development of new drugs against AD.
Butyrylcholinesterase (BChE) inhibitors were identified from a collection containing cinchonine, cinchonidine and synthetic derivatives, and further characterized using cytotoxicity and molecular docking studies. The most active ones were: (10 triple bond)-10,11-dibromo-10,11-dihydrocinchonidine (11), a competitive inhibitor with Ki = 3.45 +/- 0.39 microM, and IC50 BChE = 9.83 +/- 0.30 microM/human (h)BChE = 34.47 +/- 4.63 and O-(trimethylsilyl)cinchonine (15), a mixed inhibitor with Kiuc = 1.73 +/- 0.46 microM and Kic = 0.85 +/- 0.26 microM, and IC50 BChE = 0.56 +/- 0.14 microM/hBChE = 0.24 +/- 0.04. In cytotoxicity experiments, > or = 80% of the cells remained viable when exposed to concentrations of up to 80 microM of both inhibitors in four different cell lines, including neurons. Due to the bulkier trimethylsilyl side group of 15, it covered the active site of hBChE better than 11 with an OH-group while not being able to fit into the active site gorge of hAChE, thus explaining the selectivity of 15 towards hBChE.
The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase AChE and butyrylcholinesterase BChE inhibitory activity Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD's pathogenesis simultaneously cholinergic depletion and beta amyloid Abeta aggregation Berberin palmatine and chelerythrine chemically clustered in the so-called isoquinoline group showed promising cholinesterase inhibitory activity and were therefore further investigated Moreover the compounds demonstrated moderate to good inhibition of Abeta aggregation as well as the ability to disaggregate already preformed Abeta aggregates in an experimental set-up using HFIP as promotor of Abeta aggregates Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor Using molecular docking studies it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site PAS of the AChE In view of this we went on to investigate its effect on inhibiting Abeta aggregation stimulated by AChE Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin-chelerythrine-acting on AChE and BChE with a dual ability to inhibit Abeta aggregation as well as to disaggregate preformed Abeta aggregates This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.
