Discovery of a natural product-like iNOS inhibitor by molecular docking with potential neuroprotective effects in vivo

PLoS One. 2014 Apr 1;9(4):e92905. doi: 10.1371/journal.pone.0092905. eCollection 2014.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Animals
  • Biological Products / analysis
  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Cell Death / drug effects
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Enzyme Inhibitors / analysis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • High-Throughput Screening Assays
  • Isoenzymes / metabolism
  • Larva / drug effects
  • Larva / physiology
  • Ligands
  • Lipopolysaccharides / pharmacology
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation*
  • Motor Activity / drug effects
  • Neuroprotective Agents / analysis
  • Neuroprotective Agents / pharmacology*
  • Nitric Oxide / biosynthesis
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / metabolism
  • RAW 264.7 Cells
  • Thermodynamics
  • Zebrafish

Substances

  • Biological Products
  • Enzyme Inhibitors
  • Isoenzymes
  • Ligands
  • Lipopolysaccharides
  • Neuroprotective Agents
  • Nitric Oxide
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • 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.