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 journalArticlepeer-review

22 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of 'Structure-guided design of selective inhibitors of neuronal nitric oxide synthase'. Together they form a unique fingerprint.

Cite this