Structure-based Design of Inhibitors of Human Kynurenine Aminotransferase-I — ASN Events
  1. Schedule
  2. Session Twelve - Poster Session D including Happy Hour & Trade Display
  3. Structure-based Design of Inhibitors of Human Kynurenine Aminotransferase-I

Structure-based Design of Inhibitors of Human Kynurenine Aminotransferase-I (#407)

Naveed A Nadvi 1 2 , Fady N Akladios 2 , Jane R Hanrahan 2 , Charles A Collyer 3 , Mark D Gorrell 1 , Vimal Kapoor 4 , W Bret Church 2
  1. Centenary Institute, University of Sydney, Sydney, NSW, Australia
  2. Faculty of Pharmacy, University of Sydney, Sydney, NSW, Australia
  3. School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia
  4. School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia

High levels of kynurenic acid (KA) have been thought to accompany several psychoses, including schizophrenia. This is consistent with the role of KA as an endogenous antagonist at the glutamate-binding site of the NMDA receptor, and overactivity in the enzyme human kynurenine aminotransferase-I (hKAT-I), which produces this metabolite, could contribute to pathophysiology, making the kynurenine pathway a valuable target for the treatment of such neuropsychiatric disease. In the belief that novel inhibitors will be of value, we have been using structure-based methods to assist in the design of inhibitors of hKAT-1.
In silico screening and docking calculations have been used to suggest potential inhibitors for hKAT-1, and the synthesis of potential inhibitors and related chemically accessible variants has also been achieved. The inhibitory effects of indole based compounds have been reported, as well as a crystal structure for hKAT-1 with indole-3-acetic acid bound. In our study, we have pursued a series of phenyl hydrazone compounds and seven candidates were found to inhibit hKAT-I with the best possessing an IC50 of 19.8 µM, lower than the reported indole-3-propionic acid (IC50 of 140.0 µM). To assist in further design, we have pursued crystal structures of the enzyme in complex with our inhibitors and have been able to grow crystals diffracting to 1.2 Å resolution. Currently we have a crystal structure with another well-known enzyme family inhibitor, aminooxy-acetic acid (IC50 of 13.1 µM) bound at 1.5 Å resolution.

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  1. Fady N. Akladios, Naveed A. Nadvi, Joohong Park, Jane R. Hanrahan, Vimal Kapoor, Mark D. Gorrell, W. Bret Church (2012). Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I, Bioorganic and Medicinal Chemistry Letters, 22, 1579-1581