3TEM

Quinone Oxidoreductase (NQ02) bound to the imidazoacridin-6-one 6a1

Summary for 3TEM

• Entry DOI: 10.2210/pdb3tem/pdb
• Related: 3TE7
• Descriptor: Ribosyldihydronicotinamide dehydrogenase [quinone], ZINC ION, FLAVIN-ADENINE DINUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P16083
• Total number of polymer chains: 2
• Total formula weight: 53786.11

Authors

Dunstan, M.S.,Leys, D. (deposition date: 2011-08-15, release date: 2011-09-21, Last modification date: 2024-02-28)

Primary citation

Dunstan, M.S.,Barnes, J.,Humphries, M.,Whitehead, R.C.,Bryce, R.A.,Leys, D.,Stratford, I.J.,Nolan, K.A.
Novel Inhibitors of NRH:Quinone Oxidoreductase 2 (NQO2): Crystal Structures, Biochemical Activity, and Intracellular Effects of Imidazoacridin-6-ones.
J.Med.Chem., 54:6597-6611, 2011

PubMed Abstract: Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of NQO2 containing two of the imidazoacridin-6-ones have been solved. To generate compounds with reduced off-target (DNA binding) effects, an N-oxide moiety was introduced into the tertiary aminoalkyl side chain of the imidazoacridin-6-ones. This resulted in substantially less toxicity in a panel of eight cancer cell lines, decreased protein binding, and reduced DNA binding and nuclear accumulation. Finally, one of the N-oxides showed potent ability to inhibit the enzymatic function of NQO2 in cells, and therefore, it may be useful as a pharmacological probe to study the properties of the enzyme in vitro and in vivo.

PubMed: 21859103
DOI: 10.1021/jm200416e

Experimental method

X-RAY DIFFRACTION (1.45 Å)