4UH5

Structure of human nNOS R354A G357D mutant heme domain in complex with N1-(5-(2-(6-Amino-4-methylpyridin-2-yl)ethyl)pyridin-3-yl)-N1,N2- dimethylethane-1,2-diamine

Summary for 4UH5

• Entry DOI: 10.2210/pdb4uh5/pdb
• Related: 4UGZ 4UH0 4UH1 4UH2 4UH3 4UH4 4UH6 4UH7 4UH8 4UH9 4UHA
• Descriptor: NEURONAL NITRIC OXIDE SYNTHASE, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total)
• Functional Keywords: oxidoreductase, nitric oxide synthase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cell membrane, sarcolemma; Peripheral membrane protein: P29475
• Total number of polymer chains: 2
• Total formula weight: 100019.60

Authors

Li, H.,Poulos, T.L. (deposition date: 2015-03-23, release date: 2015-07-15, Last modification date: 2024-05-08)

Primary citation

Kang, S.,Li, H.,Tang, W.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
2-Aminopyridines with a Truncated Side Chain to Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity.
J.Med.Chem., 58:5548-, 2015

PubMed Abstract: We have analyzed a recently obtained crystal structure of human neuronal nitric oxide synthase (nNOS) and then designed and synthesized several 2-aminopyridine derivatives containing a truncated side chain to avoid the hydrophobic pocket that differentiates human and rat nNOS in an attempt to explore alternative binding poses along the substrate access channel of human nNOS. Introduction of an N-methylethane-1,2-diamine side chain and conformational constraints such as benzonitrile and pyridine as the middle aromatic linker were sufficient to increase human and rat nNOS binding affinity and inducible and endothelial NOS selectivity. We found that 14b is a potent inhibitor; the binding modes with human and rat nNOS are unexpected, inducing side chain rotamer changes in Gln478 (rat) at the top of the active site. Compound 19c exhibits Ki values of 24 and 55 nM for rat and human nNOS, respectively, with 153-fold iNOS and 1040-fold eNOS selectivity. 19c has 18% oral bioavailability.

PubMed: 26120733
DOI: 10.1021/ACS.JMEDCHEM.5B00573

Experimental method

X-RAY DIFFRACTION (1.983 Å)