9MZ3
Structure of human endothelial nitric oxide synthase heme domain bound 2-(2-amino-6-fluoro-4-methylquinolin-7-yl)-5-(2-aminoethyl)phenol
This is a non-PDB format compatible entry.
Summary for 9MZ3
| Entry DOI | 10.2210/pdb9mz3/pdb |
| Descriptor | Nitric oxide synthase, endothelial, ZINC ION, CALCIUM ION, ... (12 entities in total) |
| Functional Keywords | nitric oxide synthase inhibitor binding, oxidoreductase-inhibitor complex, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 206016.33 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2025-01-22, release date: 2025-12-03, Last modification date: 2026-04-01) |
| Primary citation | Ansari, A.,Kang, K.M.,Li, H.,Hardy, C.D.,Rathnayake, A.D.,Awasthi, A.,Poulos, T.L.,Silverman, R.B. Enhancement of Potency and Selectivity of 2-Aminoquinoline-Based Human Neuronal Nitric Oxide Synthase Inhibitors. J.Med.Chem., 69:3779-3795, 2026 Cited by PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is a key enzyme in neurodegenerative diseases and melanoma, making it an important therapeutic target. We previously reported 2-aminoquinoline-based nNOS inhibitors with promising activity but limited by suboptimal potency, isoform selectivity, and off-target effects. To address these issues, we designed and synthesized a new series of 7-aryl-6-fluoro-4-methyl-2-aminoquinoline derivatives. Compound showed excellent potency against human nNOS ( 16 nM), with ∼1800-fold selectivity over human endothelial NOS (eNOS) and ∼2900-fold over human inducible NOS (iNOS). PAMPA-BBB experiments indicated high effective permeability ( = 13.04 × 10 cm/s), suggesting strong CNS drug potential. pharmacokinetic studies in mice further demonstrated sustained systemic exposure, low clearance, and robust brain penetration. In contrast, compound , the -Me analogue of 16, was inactive. Molecular dynamics simulations indicated that -methylation disrupted the favorable solvation of the tail amino group, likely contributing to its loss of activity and nNOS affinity. PubMed: 41635994DOI: 10.1021/acs.jmedchem.5c01679 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.95 Å) |
Structure validation
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