5VUY

Structure of human neuronal nitric oxide synthase heme domain in complex with 7-(((4-(Dimethylamino)phenethyl)amino)methyl)quinolin-2-amine

Summary for 5VUY

• Entry DOI: 10.2210/pdb5vuy/pdb
• Related: 5VUV 5VUW 5VUX 5VUZ 5VV1 5VV2 5VV3 5VV4 5VV5 5VVB
• Descriptor: Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (6 entities in total)
• Functional Keywords: nitric oxide synthase inhibitor complex, heme enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 99990.73

Authors

Li, H.,Poulos, T.L. (deposition date: 2017-05-19, release date: 2017-08-16, Last modification date: 2023-10-04)

Primary citation

Pensa, A.V.,Cinelli, M.A.,Li, H.,Chreifi, G.,Mukherjee, P.,Roman, L.J.,Martasek, P.,Poulos, T.L.,Silverman, R.B.
Hydrophilic, Potent, and Selective 7-Substituted 2-Aminoquinolines as Improved Human Neuronal Nitric Oxide Synthase Inhibitors.
J. Med. Chem., 60:7146-7165, 2017

PubMed Abstract: Neuronal nitric oxide synthase (nNOS) is a target for development of antineurodegenerative agents. Most nNOS inhibitors mimic l-arginine and have poor bioavailability. 2-Aminoquinolines showed promise as bioavailable nNOS inhibitors but suffered from low human nNOS inhibition, low selectivity versus human eNOS, and significant binding to other CNS targets. We aimed to improve human nNOS potency and selectivity and reduce off-target binding by (a) truncating the original scaffold or (b) introducing a hydrophilic group to interrupt the lipophilic, promiscuous pharmacophore and promote interaction with human nNOS-specific His342. We synthesized both truncated and polar 2-aminoquinoline derivatives and assayed them against recombinant NOS enzymes. Although aniline and pyridine derivatives interact with His342, benzonitriles conferred the best rat and human nNOS inhibition. Both introduction of a hydrophobic substituent next to the cyano group and aminoquinoline methylation considerably improved isoform selectivity. Most importantly, these modifications preserved Caco-2 permeability and reduced off-target CNS binding.

PubMed: 28776992
DOI: 10.1021/acs.jmedchem.7b00835

Experimental method

X-RAY DIFFRACTION (2.154 Å)