9Q4M
Structure of human neuronal nitric oxide synthase R354A/G357D mutant heme domain bound with 6-((2,3-difluoro-5-(2-(3-fluoroazetidin-1-yl)ethyl)phenoxy)methyl)-4-methylpyridin-2-amine
This is a non-PDB format compatible entry.
Summary for 9Q4M
| Entry DOI | 10.2210/pdb9q4m/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 binding, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 201506.91 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2025-08-20, release date: 2025-09-10, Last modification date: 2026-02-25) |
| Primary citation | Ansari, A.,Chrzanowski, R.T.,Li, H.,Hardy, C.D.,Awasthi, A.,Poulos, T.L.,Silverman, R.B. Potent, Selective, and Brain Penetrant Ether-Linked 2-Aminopyridine Inhibitors of Human Neuronal Nitric Oxide Synthase with Excellent Oral Bioavailability. J.Med.Chem., 69:3506-3518, 2026 Cited by PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is a therapeutic target for the treatment of various neurological disorders and for melanoma. As part of our ongoing efforts to develop potent and selective nNOS inhibitors, we modified our previously reported compound to by introducing an ether linker, leading to a new series of ether-linked 2-aminopyridine-based compounds that exhibit high potency, isoform selectivity, and membrane permeability. Among them, lead compound inhibits human nNOS with a of 25 nM and exhibits 2300-fold selectivity over human endothelial NOS (eNOS) while also displaying high effective permeability in the parallel artificial membrane permeability assay for the blood-brain barrier (PAMPA-BBB) assay ( = 16.67 × 10 cm/s), indicating favorable blood-brain barrier penetration. Pharmacokinetic evaluation confirmed the brain penetrance of and demonstrated a high oral bioavailability (77%). Moreover, the X-ray crystal structures of representative compounds bound to three NOS isoforms (hnNOS, rnNOS, and heNOS) revealed key binding interactions that contribute to both potency and selectivity. PubMed: 41630196DOI: 10.1021/acs.jmedchem.5c03568 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.065 Å) |
Structure validation
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