TY - JOUR
T1 - Peripheral but crucial
T2 - A hydrophobic pocket (Tyr706, Leu 337, and Met336) for potent and selective inhibition of neuronal nitric oxide synthase
AU - Xue, Fengtian
AU - Li, Huiying
AU - Fang, Jianguo
AU - Roman, Linda J.
AU - Martásek, Pavel
AU - Poulos, Thomas L.
AU - Silverman, Richard B.
N1 - Funding Information:
The authors are grateful to the National Institutes of Health for financial support to R.B.S. (GM49725), T.L.P. (GM57353), and Dr. Bettie Sue Masters (GM52419, with whose laboratory P.M. and L.J.R. are affiliated). B.S.S.M. is the Robert A. Welch Distinguished Professor in Chemistry (AQ0012). P.M. is supported by Grants 0021620806 and 1M0520 from MSMT of the Czech Republic.
PY - 2010/11/1
Y1 - 2010/11/1
N2 - 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.
AB - 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.
KW - Crystal structure
KW - Nitric oxide synthase
KW - Peripheral hydrophobic pocket
KW - Pi-stacking
KW - Selective inhibitor
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U2 - 10.1016/j.bmcl.2010.08.096
DO - 10.1016/j.bmcl.2010.08.096
M3 - Article
C2 - 20833542
AN - SCOPUS:77957876680
VL - 20
SP - 6258
EP - 6261
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 21
ER -