4IMX

Structure of bovine endothelial nitric oxide synthase heme domain in complex with 3,5-bis(2-(6-amino-4-methylpyridin-2-yl)ethyl)benzonitrile

Summary for 4IMX

• Entry DOI: 10.2210/pdb4imx/pdb
• Related: 4IMS 4IMT 4IMU 4IMW
• Descriptor: subunit A, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (9 entities in total)
• Functional Keywords: oxidoreductase nitric oxide synthase, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Bos taurus (bovine)
• Total number of polymer chains: 2
• Total formula weight: 102189.96

Authors

Li, H.,Poulos, T.L. (deposition date: 2013-01-03, release date: 2013-04-24, Last modification date: 2024-02-28)

Primary citation

Huang, H.,Li, H.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Structure-guided design of selective inhibitors of neuronal nitric oxide synthase.
J.Med.Chem., 56:3024-3032, 2013

PubMed Abstract: Nitric oxide synthases (NOSs) comprise three closely related isoforms that catalyze the oxidation of L-arginine to L-citrulline and the important second messenger nitric oxide (NO). Pharmacological selective inhibition of neuronal NOS (nNOS) has the potential to be therapeutically beneficial in various neurodegenerative diseases. Here, we present a structure-guided, selective nNOS inhibitor design based on the crystal structure of lead compound 1 in nNOS. The best inhibitor, 7, exhibited low nanomolar inhibitory potency and good isoform selectivities (nNOS over eNOS and iNOS are 472-fold and 239-fold, respectively). Consistent with the good selectivity, 7 binds to nNOS and eNOS with different binding modes. The distinctly different binding modes of 7, driven by the critical residue Asp597 in nNOS, offers compelling insight to explain its isozyme selectivity, which should guide future drug design programs.

PubMed: 23451760
DOI: 10.1021/jm4000984

Experimental method

X-RAY DIFFRACTION (2.25 Å)