5VUN
Structure of rat neuronal nitric oxide synthase heme domain in complex with 7-(((3-(4-Methylpyridin-3-yl)propyl)amino)methyl)quinolin-2-amine
Summary for 5VUN
| Entry DOI | 10.2210/pdb5vun/pdb |
| Descriptor | Nitric oxide synthase, brain, PROTOPORPHYRIN IX CONTAINING FE, 5,6,7,8-TETRAHYDROBIOPTERIN, ... (8 entities in total) |
| Functional Keywords | nitric oxide synthase, inhibitor complex, heme enzyme, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor |
| Biological source | Rattus norvegicus (Rat) |
| Total number of polymer chains | 2 |
| Total formula weight | 100501.17 |
| 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 Cited by 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: 28776992DOI: 10.1021/acs.jmedchem.7b00835 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.745 Å) |
Structure validation
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