9MWS
Structure of human endothelial nitric oxide synthase heme domain bound with N-(3-(2-((3-(thiazole-5-carboximidamido)benzyl)amino)ethyl)phenyl)thiazole-5-carboximidamide
This is a non-PDB format compatible entry.
Summary for 9MWS
| Entry DOI | 10.2210/pdb9mws/pdb |
| Descriptor | Nitric oxide synthase, endothelial, CALCIUM ION, PROTOPORPHYRIN IX CONTAINING FE, ... (11 entities in total) |
| Functional Keywords | nitric oxide synthase inhibitor binding, oxidoreductase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 205843.66 |
| Authors | Li, H.,Poulos, T.L. (deposition date: 2025-01-17, release date: 2025-11-26, Last modification date: 2026-04-01) |
| Primary citation | Awasthi, A.,Patel, A.,Li, H.,Kang, K.M.,Hardy, C.D.,Ansari, A.,Nowar, R.,Hasan, M.E.,Yang, S.,Poulos, T.L.,Silverman, R.B. New Inhibitors of Neuronal Nitric Oxide Synthase for the Treatment of Melanoma. J.Med.Chem., 69:2310-2329, 2026 Cited by PubMed Abstract: In 2024, an estimated 100,640 new cases of invasive melanoma were diagnosed in the U.S., with 9290 deaths. Our previous studies revealed that neuronal nitric oxide synthase (nNOS) derived nitric oxide plays a critical role in melanoma progression, making nNOS inhibition a promising strategy. High structural similarity among NOS isoforms requires careful design of nNOS inhibitors to avoid off-target effects. Our previous lead, HH044, demonstrated potent antimelanoma activity but exhibited only moderate nNOS selectivity. Here, we utilized a structure-based approach to design nNOS inhibitors that promote interactions with human nNOS-specific residue His342. Compound exhibited inhibition of both human ( = 1.7 nM) and rat nNOS ( = 2.3 nM), with 5654-fold selectivity over human eNOS and 250-fold selectivity over iNOS. X-ray crystallography and molecular modeling revealed a novel SAR, forming the basis for nNOS inhibition and providing a foundation for further innovative design of nNOS inhibitors for melanoma treatment. PubMed: 41615895DOI: 10.1021/acs.jmedchem.5c02154 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.899 Å) |
Structure validation
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