Structure-guided design of selective inhibitors of neuronal nitric oxide synthase

He Huang, Huiying Li, Pavel Martásek, Linda J. Roman, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of l-arginine to l-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.

Original languageEnglish (US)
Pages (from-to)3024-3032
Number of pages9
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013

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Nitric Oxide Synthase Type I
Protein Isoforms
Citrulline
Drug Design
Second Messenger Systems
Nitric Oxide Synthase
Neurodegenerative Diseases
Isoenzymes
Arginine
Nitric Oxide
Pharmacology
Lead

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Huang, H., Li, H., Martásek, P., Roman, L. J., Poulos, T. L., & Silverman, R. B. (2013). Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. Journal of Medicinal Chemistry, 56(7), 3024-3032. https://doi.org/10.1021/jm4000984

Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. / Huang, He; Li, Huiying; Martásek, Pavel; Roman, Linda J.; Poulos, Thomas L.; Silverman, Richard B.

In: Journal of Medicinal Chemistry, Vol. 56, No. 7, 11.04.2013, p. 3024-3032.

Research output: Contribution to journalArticle

Huang, H, Li, H, Martásek, P, Roman, LJ, Poulos, TL & Silverman, RB 2013, 'Structure-guided design of selective inhibitors of neuronal nitric oxide synthase', Journal of Medicinal Chemistry, vol. 56, no. 7, pp. 3024-3032. https://doi.org/10.1021/jm4000984
Huang H, Li H, Martásek P, Roman LJ, Poulos TL, Silverman RB. Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. Journal of Medicinal Chemistry. 2013 Apr 11;56(7):3024-3032. https://doi.org/10.1021/jm4000984
Huang, He ; Li, Huiying ; Martásek, Pavel ; Roman, Linda J. ; Poulos, Thomas L. ; Silverman, Richard B. / Structure-guided design of selective inhibitors of neuronal nitric oxide synthase. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 7. pp. 3024-3032.
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