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 language | English (US) |
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Pages (from-to) | 6258-6261 |
Number of pages | 4 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 20 |
Issue number | 21 |
DOIs | |
State | Published - Nov 1 2010 |
Keywords
- Crystal structure
- Nitric oxide synthase
- Peripheral hydrophobic pocket
- Pi-stacking
- Selective inhibitor
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
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Dive into the research topics of 'Peripheral but crucial: A hydrophobic pocket (Tyr706, Leu 337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase'. Together they form a unique fingerprint.Datasets
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Structure of rat neuronal nitric oxide synthase heme domain complexed with 6-(((3S,4S)-4-(2-(3-Fluorophenethylamino)ethoxy)pyrrolidin-3-yl)methyl)pyridin-2-amine
Xue, F. (Contributor), Li, H. (Contributor), Fang, J. (Contributor), Roman, L. J. (Contributor), Martásek, P. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Oct 6 2010
DOI: 10.2210/pdb3NNZ/pdb, https://www.wwpdb.org/pdb?id=pdb_00003nnz
Dataset
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Structure of rat neuronal nitric oxide synthase heme domain complexed with 6-(((3R,4R)-4-(2-(3-Fluorophenethylamino)ethoxy)pyrrolidin-3-yl)methyl)pyridin-2-amine
Xue, F. (Contributor), Li, H. (Contributor), Fang, J. (Contributor), Roman, L. J. (Contributor), Martásek, P. (Contributor), Poulos, T. L. (Contributor) & Silverman, R. B. (Contributor), Protein Data Bank (PDB), Oct 6 2010
DOI: 10.2210/pdb3NNY/pdb, https://www.wwpdb.org/pdb?id=pdb_00003nny
Dataset