5ADI
Structure of human nNOS R354A G357D mutant heme domain in complex with 7-(((5-((Methylamino)methyl)pyridin-3-yl)oxy)methyl)quinolin-2- amine
Summary for 5ADI
| Entry DOI | 10.2210/pdb5adi/pdb |
| Related | 5AD4 5AD5 5AD6 5AD7 5AD8 5AD9 5ADA 5ADB 5ADC 5ADD 5ADE 5ADF 5ADG 5ADJ 5ADK 5ADL 5ADM 5ADN |
| Descriptor | NITRIC OXIDE SYNTHASE, BRAIN, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 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 | 100226.87 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2015-08-20, release date: 2015-10-28, Last modification date: 2024-05-08) |
| Primary citation | Cinelli, M.A.,Li, H.,Pensa, A.V.,Kang, S.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. J.Med.Chem., 58:8694-, 2015 Cited by PubMed Abstract: Excess nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) is implicated in neurodegenerative disorders. As a result, inhibition of nNOS and reduction of NO levels is desirable therapeutically, but many nNOS inhibitors are poorly bioavailable. Promising members of our previously reported 2-aminoquinoline class of nNOS inhibitors, although orally bioavailable and brain-penetrant, suffer from unfavorable off-target binding to other CNS receptors, and they resemble known promiscuous binders. Rearranged phenyl ether- and aniline-linked 2-aminoquinoline derivatives were therefore designed to (a) disrupt the promiscuous binding pharmacophore and diminish off-target interactions and (b) preserve potency, isoform selectivity, and cell permeability. A series of these compounds was synthesized and tested against purified nNOS, endothelial NOS (eNOS), and inducible NOS (iNOS) enzymes. One compound, 20, displayed high potency, selectivity, and good human nNOS inhibition, and retained some permeability in a Caco-2 assay. Most promisingly, CNS receptor counterscreening revealed that this rearranged scaffold significantly reduces off-target binding. PubMed: 26469213DOI: 10.1021/ACS.JMEDCHEM.5B01330 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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