Crystal structures of constitutive Nitric Oxide synthases in complex with de novo designed inhibitors

Jotaro Igarashi, Li Huiying, Joumana Jamal, Ji Haitao, Fang Jianguo, Graham R. Lawton, Richard B. Silverman, Thomas L. Poulos

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

New nitric oxide synthase (NOS) inhibitors were designed de novo with knowledge gathered from the studies on the nNOS-selective dipeptide inhibitors. Each of the new inhibitors consists of three fragments: an aminopyridine ring, a pyrrolidine, and a tail of various length and polarity. The in vitro inhibitory assays indicate good potency and isoform selectivity for some of the compounds. Crystal structures of these inhibitors bound to either wild type or mutant nNOS and eNOS have confirmed design expectations. The aminopyridine ring mimics the guanidinium group of L-arginine and functions as an anchor to place the compound in the NOS active site where it hydrogen bonds to a conserved Glu. The rigidity of the pyrrolidine ring places the pyrrolidine ring nitrogen between the same conserved Glu and the selective residue nNOS Asp597/eNOS Asn368, which results in similar interactions observed with the α-amino group of dipeptide inhibitors bound to nNOS. These structures provide additional information to help in the design of inhibitors with greater potency, physicochemical properties, and isoform selectivity.

Original languageEnglish (US)
Pages (from-to)2060-2066
Number of pages7
JournalJournal of Medicinal Chemistry
Volume52
Issue number7
DOIs
StatePublished - Apr 9 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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