6POU

Structure of human endothelial nitric oxide synthase heme domain in complex with 7-(4-(2-Aminoethyl)phenyl)-4-methylquinolin-2-amine

Summary for 6POU

• Entry DOI: 10.2210/pdb6pou/pdb
• Descriptor: Nitric oxide synthase, endothelial, PROTOPORPHYRIN IX CONTAINING FE, 7-[4-(2-aminoethyl)phenyl]-4-methylquinolin-2-amine, ... (8 entities in total)
• Functional Keywords: nitric oxide synthase inhibitor, heme enzyme, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 308899.10

Authors

Li, H.,Poulos, T.L. (deposition date: 2019-07-05, release date: 2020-04-29, Last modification date: 2023-10-11)

Primary citation

Cinelli, M.A.,Reidl, C.T.,Li, H.,Chreifi, G.,Poulos, T.L.,Silverman, R.B.
First Contact: 7-Phenyl-2-Aminoquinolines, Potent and Selective Neuronal Nitric Oxide Synthase Inhibitors That Target an Isoform-Specific Aspartate.
J.Med.Chem., 63:4528-4554, 2020

PubMed Abstract: Inhibition of neuronal nitric oxide synthase (nNOS), an enzyme implicated in neurodegenerative disorders, is an attractive strategy for treating or preventing these diseases. We previously developed several classes of 2-aminoquinoline-based nNOS inhibitors, but these compounds had drawbacks including off-target promiscuity, low activity against human nNOS, and only modest selectivity for nNOS over related enzymes. In this study, we synthesized new nNOS inhibitors based on 7-phenyl-2-aminoquinoline and assayed them against rat and human nNOS, human eNOS, and murine and (in some cases) human iNOS. Compounds with a -relationship between the aminoquinoline and a positively charged tail moiety were potent and had up to nearly 900-fold selectivity for human nNOS over human eNOS. X-ray crystallography indicates that the amino groups of some compounds occupy a water-filled pocket surrounding an nNOS-specific aspartate residue (absent in eNOS). This interaction was confirmed by mutagenesis studies, making 7-phenyl-2-aminoquinolines the first aminoquinolines to interact with this residue.

PubMed: 32302123
DOI: 10.1021/acs.jmedchem.9b01573

Experimental method

X-RAY DIFFRACTION (2.194 Å)