9C1Z
Structure of human endothelial nitric oxide synthase heme domain in complex with 7-((3-(((4-(6-aminopyridin-2-yl)butyl)amino)methyl)phenoxy)methyl)quinolin-2-amine
Summary for 9C1Z
| Entry DOI | 10.2210/pdb9c1z/pdb |
| Descriptor | Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 7-{[3-({[4-(6-aminopyridin-2-yl)butyl]amino}methyl)phenoxy]methyl}quinolin-2-amine, ... (9 entities in total) |
| Functional Keywords | nitric oxide synthase inhibitor heme enzymes, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 205013.69 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2024-05-30, release date: 2025-06-11, Last modification date: 2025-08-06) |
| Primary citation | Weerawarna, P.M.,Li, H.,Rathnayake, A.D.,Hardy, C.D.,Poulos, T.L.,Silverman, R.B. A Tetrahydrobiopterin-Displacing Potent Neuronal Nitric Oxide Synthase Inhibitor with an Unprecedented Binding Mode. Acs Med.Chem.Lett., 16:651-659, 2025 Cited by PubMed Abstract: Nitric oxide synthase (NOS) is a pivotal enzyme that regulates various physiological processes, and the dysregulation of neuronal NOS (nNOS) is implicated in neurodegenerative diseases. In our efforts to leverage existing X-ray crystallography data to develop novel aminoquinoline-pyridine hybrid inhibitors and evaluate their inhibitory activities and interactions with NOS isoforms, we identified compounds and as potent human nNOS inhibitors ( = 38 and 22 nM, respectively). Notably, compound displayed an unprecedented binding mode, displacing the essential cofactor tetrahydrobiopterin (HB). Furthermore, compound exhibited excellent selectivity, with a 900-fold preference for human nNOS over human eNOS, making it one of the most potent and selective aminoquinoline-based nNOS inhibitors reported to date. Herein we present our inhibitor design rationale, the synthesis, and the biochemical/physical evaluation of binding along with X-ray crystallographic studies with three NOS isoforms, providing detailed insights into the observed potency and selectivity of these inhibitors. PubMed: 40236557DOI: 10.1021/acsmedchemlett.5c00062 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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