Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu 337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase

Fengtian Xue, Huiying Li, Jianguo Fang, Linda J. Roman, Pavel Martásek, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Selective inhibition of the neuronal isoform of nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) has become a promising strategy for the discovery of new therapeutic agents for neurodegenerative diseases. However, because of the high sequence homology of different isozymes in the substrate binding pocket, developing inhibitors with both potency and excellent isoform selectivity remains a challenging problem. Herein, we report the evaluation of a recently discovered peripheral hydrophobic pocket (Tyr706, Leu337, and Met336) that opens up upon inhibitor binding and its potential in designing potent and selective nNOS inhibitors using three compounds, 2a, 2b, and 3. Crystal structure results show that inhibitors 2a and 3 adopted the same binding mode as lead compound 1. We also found that hydrophobic interactions between the 4-methyl group of the aminopyridine ring of these compounds with the side chain of Met336, as well as the π-π stacking interaction between the pyridinyl motif and the side chain of Tyr706 are important for the high potency and selectivity of these nNOS inhibitors.

Original languageEnglish (US)
Pages (from-to)6258-6261
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume20
Issue number21
DOIs
StatePublished - Nov 1 2010

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Nitric Oxide Synthase Type I
Protein Isoforms
Nitric Oxide Synthase
Aminopyridines
Neurodegenerative diseases
Lead compounds
Nitric Oxide Synthase Type III
Nitric Oxide Synthase Type II
Sequence Homology
Hydrophobic and Hydrophilic Interactions
Neurodegenerative Diseases
Isoenzymes
Crystal structure
Substrates
Therapeutics

Keywords

  • Crystal structure
  • Nitric oxide synthase
  • Peripheral hydrophobic pocket
  • Pi-stacking
  • Selective inhibitor

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Peripheral but crucial : A hydrophobic pocket (Tyr706, Leu 337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase. / Xue, Fengtian; Li, Huiying; Fang, Jianguo; Roman, Linda J.; Martásek, Pavel; Poulos, Thomas L.; Silverman, Richard B.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 21, 01.11.2010, p. 6258-6261.

Research output: Contribution to journalArticle

Xue, Fengtian ; Li, Huiying ; Fang, Jianguo ; Roman, Linda J. ; Martásek, Pavel ; Poulos, Thomas L. ; Silverman, Richard B. / Peripheral but crucial : A hydrophobic pocket (Tyr706, Leu 337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase. In: Bioorganic and Medicinal Chemistry Letters. 2010 ; Vol. 20, No. 21. pp. 6258-6261.
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