6ngc

Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(3-(3-(dimethylamino)propyl)-2,5,6-trifluorophenethyl)-4-methylpyridin-2-amineStructure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 6-(3-(3-(dimethylamino)propyl)-2,5,6-trifluorophenethyl)-4-methylpyridin-2-amine

Structural highlights

6ngc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.998Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NOS1_HUMAN Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In the brain and peripheral nervous system, NO displays many properties of a neurotransmitter. Probably has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such SRR.

Publication Abstract from PubMed

Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the p Ka of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency ( Ki < 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.

Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold.,Do HT, Li H, Chreifi G, Poulos TL, Silverman RB J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b02032

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OCA

[1] Do HT, Li H, Chreifi G, Poulos TL, Silverman RB. Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold. J Med Chem. 2019 Feb 25. doi: 10.1021/acs.jmedchem.8b02032. PMID:30802056 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b02032

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