4CAP
Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(2-(3-(3-Fluorophenyl(propylamino)methyl))quinolin-2- amine
Summary for 4CAP
| Entry DOI | 10.2210/pdb4cap/pdb |
| Related | 4CAM 4CAN 4CAO 4CAQ 4CAR 4CDT 4CFT |
| Descriptor | NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total) |
| Functional Keywords | oxidoreductase, nitric oxide synthase, inhibitor complex |
| Biological source | RATTUS NORVEGICUS (NORWAY RAT) |
| Cellular location | Cell membrane, sarcolemma; Peripheral membrane protein (By similarity): P29476 |
| Total number of polymer chains | 2 |
| Total formula weight | 100142.78 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2013-10-08, release date: 2014-02-19, Last modification date: 2024-05-08) |
| Primary citation | Cinelli, M.A.,Li, H.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B. Simplified 2-Aminoquinoline-Based Scaffold for Potent and Selective Neuronal Nitric Oxide Synthase Inhibition. J.Med.Chem., 57:1513-, 2014 Cited by PubMed Abstract: Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability. PubMed: 24472039DOI: 10.1021/JM401838X PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.06 Å) |
Structure validation
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