4GEB

Kynurenine Aminotransferase II Inhibitors

Summary for 4GEB

• Entry DOI: 10.2210/pdb4geb/pdb
• Related: 4GDY 4GE4 4GE7 4GE9
• Descriptor: Kynurenine/alpha-aminoadipate aminotransferase, mitochondrial, (5-hydroxy-4-{[(7-hydroxy-6-oxo-2-phenyl-6,7-dihydro-2H-pyrazolo[3,4-b]pyridin-5-yl)amino]methyl}-6-methylpyridin-3-yl)methyl dihydrogen phosphate, SULFATE ION, ... (4 entities in total)
• Functional Keywords: aminotransferase, irreversible inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Mitochondrion (Potential): Q8N5Z0
• Total number of polymer chains: 2
• Total formula weight: 99231.15

Authors

Pandit, J. (deposition date: 2012-08-01, release date: 2013-03-20, Last modification date: 2023-09-13)

Primary citation

Dounay, A.B.,Anderson, M.,Bechle, B.M.,Evrard, E.,Gan, X.,Kim, J.Y.,McAllister, L.A.,Pandit, J.,Rong, S.,Salafia, M.A.,Tuttle, J.B.,Zawadzke, L.E.,Verhoest, P.R.
PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency.
Bioorg.Med.Chem.Lett., 23:1961-1966, 2013

PubMed Abstract: The structure-based design, synthesis, and biological evaluation of a new pyrazole series of irreversible KAT II inhibitors are described herein. The modification of the inhibitor scaffold of 1 and 2 from a dihydroquinolinone core to a tetrahydropyrazolopyridinone core led to discovery of a new series of potent KAT II inhibitors with excellent physicochemical properties. Compound 20 is the most potent and lipophilically efficient of these new pyrazole analogs, with a k(inact)/K(i) value of 112,000 M(-1)s(-1) and lipophilic efficiency (LipE) of 8.53. The X-ray crystal structure of 20 with KAT II demonstrates key features that contribute to this remarkable potency and binding efficiency.

PubMed: 23466229
DOI: 10.1016/j.bmcl.2013.02.039

Experimental method

X-RAY DIFFRACTION (2.15 Å)