The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening
| Autor: | Alan P. Robertson, Richard J. Martin, Fudan Zheng, Edward W. Yu, Melanie Abongwa |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Patch-Clamp Techniques Xenopus Receptors Nicotinic Pharmacology Ligands Torpedo Drug Delivery Systems 0302 clinical medicine Tetrahydroisoquinolines Drug Discovery Pharmacology (medical) Nicotinic Agonists Receptor Ascaris suum Butaclamol Orthosteric site Drug discovery Homology modeling (+) principal subunit 3. Good health Structure-based drug discovery Nicotinic acetylcholine receptor Infectious Diseases Nicotinic agonist TID transmembrane and intracellular domain Allosteric Site Xenopus expression Allosteric modulator Allosteric regulation Biology Article lcsh:Infectious and parasitic diseases Inhibitory Concentration 50 03 medical and health sciences Allosteric Regulation Isonipecotic Acids Nitriles Asu-ACR-16 Animals Humans Computer Simulation lcsh:RC109-216 NAM negative allosteric modulator Fluorenes Virtual screening (−) complementary subunit Binding Sites nAChR nicotinic acetylcholine receptor biology.organism_classification ECD extracellular domain 030104 developmental biology Oocytes Parasitology AChBP acetylcholine-binding protein 030217 neurology & neurosurgery |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance, Vol 6, Iss 1, Pp 60-73 (2016) International Journal for Parasitology: Drugs and Drug Resistance |
| ISSN: | 2211-3207 |
| Popis: | 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. Graphical abstract Highlights • Three-dimensional structural models of the Ascaris nicotinic (Asu-ACR-16) receptor made by homology modeling. • High affinity ligands selected by in silico screening. • Four ligands validated by electrophysiological studies as negative allosteric modulators. |
| Databáze: | OpenAIRE |
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