9WHC

Crystal structure of human nNOS PDZ domain in complex with compound N28

This is a non-PDB format compatible entry.

Summary for 9WHC

• Entry DOI: 10.2210/pdb9whc/pdb
• Descriptor: Nitric oxide synthase 1, 8-fluoranyl-6-[(2-fluoranyl-4-methyl-phenyl)methyl]-1,2$l^{6},3-benzoxathiazine 2,2-dioxide (2 entities in total)
• Functional Keywords: inhibitor, complex, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 41215.60

Authors

Zhang, L.,Yang, S. (deposition date: 2025-08-26, release date: 2026-07-08)

Primary citation

Zhang, L.,Xiong, Z.,Chen, S.,Zhu, Q.,Wang, Y.,Lu, Q.,Bu, X.,Xia, A.,Chen, L.,Chen, C.,Shao, Z.,Li, L.,Yang, S.
Identification of a Potent and Selective Small-Molecule Inhibitor Targeting the nNOS-PDZ Domain that Exhibits Rapid In Vivo Antidepressant Efficacy.
J.Med.Chem., 69:14513-14529, 2026

PubMed Abstract: The PDZ domain of neuronal nitric oxide synthase (nNOS-PDZ) plays a crucial role in regulating serotonin signaling in the forebrain and has emerged as a promising target for developing rapid-acting antidepressants. Here, we report the identification of , a potent and selective small-molecule inhibitor of nNOS-PDZ. induces a substantial thermal shift (Δ) of 5.44 °C in a differential scanning fluorimetry (DSF) assay and displays an IC of 0.76 ± 0.07 μM in a fluorescence polarization (FP) assay. The cocrystal structure of the nNOS-PDZ- complex reveals key binding interactions. , produces rapid, dose-dependent antidepressant effects in mouse models of depression induced by chronic unpredictable mild stress (CUMS) and chronic corticosterone treatment, with no evidence of addictive potential or motility-related side effects. Together, these results establish as a potent and selective nNOS-PDZ inhibitor, providing a promising lead compound for the development of antidepressants.

PubMed: 42234972
DOI: 10.1021/acs.jmedchem.6c00391

Experimental method

X-RAY DIFFRACTION (2.8 Å)