6AUW
Structure of rat neuronal nitric oxide synthase heme domain in complex with 4-Methyl-6-(2-(5-(4-((methylamino)methyl)phenyl)pyridin-3-yl)ethyl)pyridin-2-amine
Summary for 6AUW
| Entry DOI | 10.2210/pdb6auw/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 | Rattus norvegicus (Rat) |
| Total number of polymer chains | 2 |
| Total formula weight | 100188.90 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2017-09-01, release date: 2018-07-11, Last modification date: 2023-10-04) |
| Primary citation | Do, H.T.,Wang, H.Y.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B. Improvement of Cell Permeability of Human Neuronal Nitric Oxide Synthase Inhibitors Using Potent and Selective 2-Aminopyridine-Based Scaffolds with a Fluorobenzene Linker. J. Med. Chem., 60:9360-9375, 2017 Cited by PubMed Abstract: Inhibition of neuronal nitric oxide synthase (nNOS) is a promising therapeutic approach to treat neurodegenerative diseases. Recently, we have achieved considerable progress in improving the potency and isoform selectivity of human nNOS inhibitors bearing a 2-aminopyridine scaffold. However, these inhibitors still suffered from too low cell membrane permeability to enter into CNS drug development. We report herein our studies to improve permeability of nNOS inhibitors as measured by both PAMPA-BBB and Caco-2 assays. The most permeable compound (12) in this study still preserves excellent potency with human nNOS (K = 30 nM) and very high selectivity over other NOS isoforms, especially human eNOS (hnNOS/heNOS = 2799, the highest hnNOS/heNOS ratio we have obtained to date). X-ray crystallographic analysis reveals that 12 adopts a similar binding mode in both rat and human nNOS, in which the 2-aminopyridine and the fluorobenzene linker form crucial hydrogen bonds with glutamate and tyrosine residues, respectively. PubMed: 29091437DOI: 10.1021/acs.jmedchem.7b01356 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.7 Å) |
Structure validation
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