Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase

Bessie N A Mbadugha, Jiwon Seo, Haitao Ji, Pavel Martásek, Linda J. Roman, Thomas M. Shea, Huiying Li, Thomas L. Poulos, Richard B. Silverman

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The X-ray structure of previously studied dipeptidomimetic inhibitors bound in the active site of neuronal nitric oxide synthase (nNOS) presented a possibility for optimizing the strength of enzyme-inhibitor interactions as well as for enhancing bioavailability. These desirable properties may be attainable by replacement of the terminal amino group of the parent compounds (1-6) with a hydroxyl group (11-13, and 18-20). The hypothesized effect would be twofold: first, a change from a positively charged amino group to a neutral hydroxyl group might afford more drug-like character and blood-brain barrier permeability to the inhibitors; second, as suggested by docking studies, the incorporated hydroxyl group might displace an active site water molecule with which the terminal amino group of the original compounds indirectly hydrogen bonds. In vitro activity assays of the hydroxyl-terminated analogs (11-13 and 18-20) showed greater than an order of magnitude increase in Ki values (decreased potency) relative to the amino-terminated compounds. These experimental data support the importance to enzyme binding of a potential electrostatic interaction relative to a hydrogen bonding interaction.

Original languageEnglish (US)
Pages (from-to)3681-3690
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume14
Issue number11
DOIs
StatePublished - Jun 1 2006

Fingerprint

Peptidomimetics
Nitric Oxide Synthase Type I
Hydroxyl Radical
Catalytic Domain
Hydrogen bonds
Enzyme Inhibitors
Hydrogen Bonding
Coulomb interactions
Blood-Brain Barrier
Static Electricity
Biological Availability
Hydrogen
Permeability
Assays
X-Rays
X rays
Molecules
Water
Enzymes
Pharmaceutical Preparations

Keywords

  • Computer modeling
  • Enzyme inhibitors
  • Hydroxyl-terminated
  • Neuronal nitric oxide synthase
  • Nitric oxide synthase
  • Peptidomimetic

ASJC Scopus subject areas

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

Cite this

Mbadugha, B. N. A., Seo, J., Ji, H., Martásek, P., Roman, L. J., Shea, T. M., ... Silverman, R. B. (2006). Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase. Bioorganic and Medicinal Chemistry, 14(11), 3681-3690. https://doi.org/10.1016/j.bmc.2006.01.044

Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase. / Mbadugha, Bessie N A; Seo, Jiwon; Ji, Haitao; Martásek, Pavel; Roman, Linda J.; Shea, Thomas M.; Li, Huiying; Poulos, Thomas L.; Silverman, Richard B.

In: Bioorganic and Medicinal Chemistry, Vol. 14, No. 11, 01.06.2006, p. 3681-3690.

Research output: Contribution to journalArticle

Mbadugha, BNA, Seo, J, Ji, H, Martásek, P, Roman, LJ, Shea, TM, Li, H, Poulos, TL & Silverman, RB 2006, 'Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase', Bioorganic and Medicinal Chemistry, vol. 14, no. 11, pp. 3681-3690. https://doi.org/10.1016/j.bmc.2006.01.044
Mbadugha, Bessie N A ; Seo, Jiwon ; Ji, Haitao ; Martásek, Pavel ; Roman, Linda J. ; Shea, Thomas M. ; Li, Huiying ; Poulos, Thomas L. ; Silverman, Richard B. / Hydroxyl-terminated peptidomimetic inhibitors of neuronal nitric oxide synthase. In: Bioorganic and Medicinal Chemistry. 2006 ; Vol. 14, No. 11. pp. 3681-3690.
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