Abstract
In this study, we applied structure-based virtual screening techniques to identify natural product or natural product-like inhibitors of iNOS. The iNOS inhibitory activity of the hit compounds was characterized using cellular assays and an in vivo zebrafish larvae model. The natural product-like compound 1 inhibited NO production in LPS-stimulated Raw264.7 macrophages, without exerting cytotoxic effects on the cells. Significantly, compound 1 was able to reverse MPTP-induced locomotion deficiency and neurotoxicity in an in vivo zebrafish larval model. Hence, compound 1 could be considered as a scaffold for the further development of iNOS inhibitors for potential anti-inflammatory or anti-neurodegenerative applications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Animals
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Biological Products / analysis
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Biological Products / chemistry
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Biological Products / pharmacology*
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Cell Death / drug effects
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / pathology
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Dose-Response Relationship, Drug
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Drug Discovery*
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / analysis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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High-Throughput Screening Assays
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Isoenzymes / metabolism
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Larva / drug effects
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Larva / physiology
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Ligands
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / metabolism
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Mice
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Molecular Conformation
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Molecular Docking Simulation*
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Motor Activity / drug effects
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Neuroprotective Agents / analysis
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Neuroprotective Agents / pharmacology*
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase Type II / antagonists & inhibitors*
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Nitric Oxide Synthase Type II / metabolism
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RAW 264.7 Cells
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Thermodynamics
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Zebrafish
Substances
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Biological Products
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Enzyme Inhibitors
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Isoenzymes
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Ligands
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Lipopolysaccharides
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Neuroprotective Agents
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Nitric Oxide
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
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Nitric Oxide Synthase Type II
Grants and funding
This work is supported by Hong Kong Baptist University (FRG2/12-13/021), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIR-SCM, HKBU), the Health and Medical Research Fund (HMRF/13121482), the Research Grants Council (HKBU/201811, HKBU/204612 and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12), the Science and Technology Development Fund, Macao SAR (001/2012/A and 103/2012/A3) and the University of Macau (MYRG091(Y2-L2)-ICMS12-LCH, MYRG121(Y2-L2)-ICMS12-LCH and MRG023/LCH/2013/ICMS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.