4D2Z
Structure of rat neuronal nitric oxide synthase heme domain in complex with (1S,2S)-2-(3-fluorobenzyl)-N-{2-[2-(1H-imidazol-1-YL)pyrimidin-4-YL]ethyl}cyclopropanamine
Summary for 4D2Z
| Entry DOI | 10.2210/pdb4d2z/pdb |
| Related | 4D2Y 4D30 4D31 4D32 4D33 4D34 4D35 4D36 4D37 4D38 4D39 4D3A 4D3B 4V3U 4V3V 4V3W 4V3X 4V3Y 4V3Z |
| 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 : P29476 |
| Total number of polymer chains | 2 |
| Total formula weight | 100198.81 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2014-10-20, release date: 2014-12-24, Last modification date: 2024-05-08) |
| Primary citation | Mukherjee, P.,Li, H.,Sevrioukova, I.,Chreifi, G.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B. Novel 2,4-Disubstituted Pyrimidines as Potent, Selective, and Cell-Permeable Inhibitors of Neuronal Nitric Oxide Synthase. J.Med.Chem., 58:1067-, 2015 Cited by PubMed Abstract: Selective inhibition of neuronal nitric oxide synthase (nNOS) is an important therapeutic approach to target neurodegenerative disorders. However, the majority of the nNOS inhibitors developed are arginine mimetics and, therefore, suffer from poor bioavailability. We designed a novel strategy to combine a more pharmacokinetically favorable 2-imidazolylpyrimidine head with promising structural components from previous inhibitors. In conjunction with extensive structure-activity studies, several highly potent and selective inhibitors of nNOS were discovered. X-ray crystallographic analysis reveals that these type II inhibitors utilize the same hydrophobic pocket to gain strong inhibitory potency (13), as well as high isoform selectivity. Interestingly, select compounds from this series (9) showed good permeability and low efflux in a Caco-2 assay, suggesting potential oral bioavailability, and exhibited minimal off-target binding to 50 central nervous system receptors. Furthermore, even with heme-coordinating groups in the molecule, modifying other pharmacophoric fragments minimized undesirable inhibition of cytochrome P450s from human liver microsomes. PubMed: 25489882DOI: 10.1021/JM501719E PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.886 Å) |
Structure validation
Download full validation report
