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 language | English (US) |
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Pages (from-to) | 2060-2066 |
Number of pages | 7 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 7 |
DOIs | |
State | Published - Apr 9 2009 |
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
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Dive into the research topics of 'Crystal structures of constitutive Nitric Oxide synthases in complex with de novo designed inhibitors'. Together they form a unique fingerprint.Datasets
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Structure of neuronal nos heme domain in complex with a inhibitor (+-)-n1-{cis-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-n2-(4'-chlorobenzyl)ethane-1,2-diamine
Igarashi, J. (Contributor), Huiying, L. (Contributor), Jamal, J. (Contributor), Haitao, J. (Contributor), Jianguo, F. (Contributor), Lawton, G. R. (Contributor), Silverman, R. B. (Contributor) & Poulos, T. L. (Contributor), Protein Data Bank (PDB), Nov 4 2008
DOI: 10.2210/pdb3B3P/pdb, https://www.wwpdb.org/pdb?id=pdb_00003b3p
Dataset
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Structure of endothelial NOS heme domain in complex with a inhibitor (+-)-N1-{cis-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-N2-(4'-chlorobenzyl)ethane-1,2-diamine
Igarashi, J. (Contributor), Huiying, L. (Contributor), Jamal, J. (Contributor), Haitao, J. (Contributor), Jianguo, F. (Contributor), Lawton, G. R. (Contributor), Silverman, R. B. (Contributor) & Poulos, T. L. (Contributor), Protein Data Bank (PDB), Mar 31 2009
DOI: 10.2210/pdb3DQS/pdb, https://www.wwpdb.org/pdb?id=pdb_00003dqs
Dataset
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Structure of endothelial NOS heme domain in complex with a inhibitor (+-)-N1-{trans-4'-[(6"-amino-4"-methylpyridin-2"-yl)methyl]pyrrolidin-3'-yl}-N2-(3'-chlorobenzyl)ethane-1,2-diamine
Igarashi, J. (Contributor), Huiying, L. (Contributor), Jamal, J. (Contributor), Haitao, J. (Contributor), Jianguo, F. (Contributor), Lawton, G. R. (Contributor), Silverman, R. B. (Contributor) & Poulos, T. L. (Contributor), Protein Data Bank (PDB), Mar 31 2009
DOI: 10.2210/pdb3DQT/pdb, https://www.wwpdb.org/pdb?id=pdb_00003dqt
Dataset