4UCH

Structure of human nNOS R354A G357D mutant heme domain in complex with 3-(((2-((2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL)ETHYL)AMINO)METHYL) BENZONITRILE

Summary for 4UCH

• Entry DOI: 10.2210/pdb4uch/pdb
• Descriptor: NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane, sarcolemma; Peripheral membrane protein: P29475
• Total number of polymer chains: 2
• Total formula weight: 100072.67

Authors

Li, H.,Poulos, T.L. (deposition date: 2014-12-03, release date: 2014-12-24, Last modification date: 2023-12-20)

Primary citation

Mukherjee, P.,Li, H.,Sevrioukova, I.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase.
J.Med.Chem., 58:1067-, 2015

PubMed Abstract: Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes.

PubMed: 25489882
DOI: 10.1021/JM501719E

Experimental method

X-RAY DIFFRACTION (2.2 Å)