5UO1
Structure of human neuronal nitric oxide synthase heme domain in complex with 3-[(2-aminoquinolin-7-yl)methoxy]-5-((methylamino)methyl)benzonitrile
Summary for 5UO1
| Entry DOI | 10.2210/pdb5uo1/pdb |
| Related | 5UNR 5UNS 5UNT 5UNU 5UNV 5UNW 5UNX 5UNY 5UNZ 5UO0 5UO2 5UO3 5UO4 5UO5 5UO6 5UO7 5UO8 5UO9 5UOA 5UOB 5UOC 5UOD |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total) |
| Functional Keywords | nitric, oxide, synthase, inhibitor, complex, heme, enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 100078.71 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2017-01-31, release date: 2017-05-03, Last modification date: 2023-10-04) |
| Primary citation | Cinelli, M.A.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. J. Med. Chem., 60:3958-3978, 2017 Cited by PubMed Abstract: Neuronal nitric oxide synthase (nNOS) inhibition is a promising strategy to treat neurodegenerative disorders, but the development of nNOS inhibitors is often hindered by poor pharmacokinetics. We previously developed a class of membrane-permeable 2-aminoquinoline inhibitors and later rearranged the scaffold to decrease off-target binding. However, the resulting compounds had decreased permeability, low human nNOS activity, and low selectivity versus human eNOS. In this study, 5-substituted phenyl ether-linked aminoquinolines and derivatives were synthesized and assayed against purified NOS isoforms. 5-Cyano compounds are especially potent and selective rat and human nNOS inhibitors. Activity and selectivity are mediated by the binding of the cyano group to a new auxiliary pocket in nNOS. Potency was enhanced by methylation of the quinoline and by introduction of simple chiral moieties, resulting in a combination of hydrophobic and auxiliary pocket effects that yielded high (∼500-fold) n/e selectivity. Importantly, the Caco-2 assay also revealed improved membrane permeability over previous compounds. PubMed: 28422508DOI: 10.1021/acs.jmedchem.7b00259 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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