6PNA
Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain in complex with 7-(4-(2-Aminoethyl)phenyl)-4-methylquinolin-2-amine
Summary for 6PNA
| Entry DOI | 10.2210/pdb6pna/pdb |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (7 entities in total) |
| Functional Keywords | nitric oxide synthase inhibitor, heme enzyme, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 99996.69 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2019-07-02, release date: 2020-04-29, Last modification date: 2023-10-11) |
| Primary citation | Cinelli, M.A.,Reidl, C.T.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B. First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate. J.Med.Chem., 63:4528-4554, 2020 Cited by PubMed Abstract: Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a -relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue. PubMed: 32302123DOI: 10.1021/acs.jmedchem.9b01573 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
Download full validation report
