Crystal Structure-Based Selective Targeting of the Pyridoxal 5′-Phosphate Dependent Enzyme Kynurenine Aminotransferase II for Cognitive Enhancement

• Published in: Journal of medicinal chemistry Vol. 53; no. 15; pp. 5684 - 5689
• Main Authors: Rossi, Franca, Valentina, Casazza, Garavaglia, Silvia, Sathyasaikumar, Korrapati V, Schwarcz, Robert, Kojima, Shin-ichi, Okuwaki, Keisuke, Ono, Shin-ichiro, Kajii, Yasushi, Rizzi, Menico
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 12-08-2010
• Subjects: Adult; Brain - drug effects; Brain - enzymology; Crystallography, X-Ray; Fluoroquinolones - chemistry; Fluoroquinolones - pharmacology; Humans; In Vitro Techniques; Models, Molecular; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Piperazines - chemistry; Piperazines - pharmacology; Protein Conformation; Pyridoxal Phosphate - physiology; Stereoisomerism; Transaminases - antagonists & inhibitors; Transaminases - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm100464k

Fluctuations in the brain levels of the neuromodulator kynurenic acid may control cognitive processes and play a causative role in several catastrophic brain diseases. Elimination of the pyridoxal 5′-phosphate dependent enzyme kynurenine aminotransferase II reduces cerebral kynurenic acid synthesis and has procognitive effects. The present description of the crystal structure of human kynurenine aminotransferase II in complex with its potent and specific primary amine-bearing fluoroquinolone inhibitor (S)-(−)-9-(4-aminopiperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-azaphenalene-5-carboxylic acid (BFF-122) should facilitate the structure-based development of cognition-enhancing drugs. From a medicinal chemistry perspective our results demonstrate that the issue of inhibitor specificity for highly conserved PLP-dependent enzymes could be successfully addressed.