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Mar. Drugs 2014, 12(4), 2114-2131; doi:10.3390/md12042114

Insights and Ideas Garnered from Marine Metabolites for Development of Dual-Function Acetylcholinesterase and Amyloid-β Aggregation Inhibitors

1
Department of Chemistry and Biochemistry, University of Mississippi, 409 Coulter Hall, University, MS 38677, USA
2
Department of Pharmacognosy, University of Mississippi, 407 Faser Hall, University, MS 38677, USA
*
Author to whom correspondence should be addressed.
Received: 10 December 2013 / Revised: 27 February 2014 / Accepted: 12 March 2014 / Published: 4 April 2014
(This article belongs to the Collection Bioactive Compounds from Marine Invertebrates)
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Abstract

Due to the diversity of biological activities that can be found in aquatic ecosystems, marine metabolites have been an active area of drug discovery for the last 30 years. Marine metabolites have been found to inhibit a number of enzymes important in the treatment of human disease. Here, we focus on marine metabolites that inhibit the enzyme acetylcholinesterase, which is the cellular target for treatment of early-stage Alzheimer’s disease. Currently, development of anticholinesterase drugs with improved potency, and drugs that act as dual acetylcholinesterase and amyloid-β aggregation inhibitors, are being sought to treat Alzheimer’s disease. Seven classes of marine metabolites are reported to possess anti-cholinesterase activity. We compared these metabolites to clinically-used acetylcholinesterase inhibitors having known mechanisms of inhibition. We performed a docking simulation and compared them to published experimental data for each metabolite to determine the most likely mechanism of inhibition for each class of marine inhibitor. Our results indicate that several marine metabolites bind to regions of the acetylcholinesterase active site that are not bound by the clinically-used drugs rivastigmine, galanthamine, donepezil, or tacrine. We use the novel poses adopted for computational drug design of tighter binding anticholinesterase drugs likely to act as inhibitors of both acetylcholinesterase activity and amyloid-β aggregation inhibition. View Full-Text
Keywords: molecular docking; enzyme inhibitor; sesquiterpene acetate; pyrrole; tetrazacyclopentazulene; bromotyrosine derivative; plastoquinone; farnesylacetone molecular docking; enzyme inhibitor; sesquiterpene acetate; pyrrole; tetrazacyclopentazulene; bromotyrosine derivative; plastoquinone; farnesylacetone
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This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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MDPI and ACS Style

Stoddard, S.V.; Hamann, M.T.; Wadkins, R.M. Insights and Ideas Garnered from Marine Metabolites for Development of Dual-Function Acetylcholinesterase and Amyloid-β Aggregation Inhibitors. Mar. Drugs 2014, 12, 2114-2131.

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