The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening
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2016-02-26
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Elsevier Ltd on behalf of Australian Society for Parasitology
Abstract
Soil-transmitted helminth infections in humans and livestock cause significant debility, reduced productivity and economic losses globally. There are a limited number of effective anthelmintic drugs available for treating helminths infections, and their frequent use has led to the development of resistance in many parasite species. There is an urgent need for novel therapeutic drugs for treating these parasites. We have chosen the ACR-16 nicotinic acetylcholine receptor of Ascaris suum (Asu-ACR-16), as a drug target and have developed three-dimensional models of this transmembrane protein receptor to facilitate the search for new bioactive compounds. Using the human α7 nAChR chimeras and Torpedo marmorata nAChR for homology modeling, we defined orthosteric and allosteric binding sites on the Asu-ACR-16 receptor for virtual screening. We identified four ligands that bind to sites on Asu-ACR-16 and tested their activity using electrophysiological recording from Asu-ACR-16 receptors expressed in Xenopus oocytes. The four ligands were acetylcholine inhibitors (SB-277011-A, IC50, 3.12 ± 1.29 μM; (+)-butaclamol Cl, IC50, 9.85 ± 2.37 μM; fmoc-1, IC50, 10.00 ± 1.38 μM; fmoc-2, IC50, 16.67 ± 1.95 μM) that behaved like negative allosteric modulators. Our work illustrates a structure-based in silico screening method for seeking anthelmintic hits, which can then be tested electrophysiologically for further characterization.
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This is a manuscript of an article published as Zheng, Fudan, Alan P. Robertson, Melanie Abongwa, Edward W. Yu, and Richard J. Martin. "The Ascaris suum nicotinic receptor, ACR-16, as a drug target: four novel negative allosteric modulators from virtual screening." International Journal for Parasitology: Drugs and Drug Resistance 6, no. 1 (2016): 60-73.
doi: https://doi.org/10.1016/j.ijpddr.2016.02.001.
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© 2016 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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Funding
The research funding was by The HatchAct, State of Iowa, and by NIH grants R01 AI047194 (to RJM) and AI114629 (to EWY) of the National Institute of Allergy and Infectious Diseases. The funding agencies had no role in the design, execution or publication of this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Disases.