Structure-based drug design with Kynurenine Aminotransferase-2

Summary

Human kynurenine amino transferase-2 (KAT-2) forms the basis of a structure-based drug design study with implications for schizophrenia and gender differences.  The various aspects of structure-based drug design in this project will appeal from those with good general laboratory skills wanting to learn more, to those with programming skills and interest in computation and biology.

Supervisor(s)

Dr W Bret Church

Research Location

Sydney Pharmacy School

Program Type

Masters/PHD

Synopsis

Schizophrenia is a psychosis that affects 1% of the population worldwide. The molecular mechanisms that trigger schizophrenia remain elusive. Several environmental risk factors have been considered, however studies performed with twins suggest that it is a significantly heritable disease. The dopamine and serotoninergic systems (dopaminergic hyperactivity) have been central, but there is additional involvement of the glutamatergic neurotransmission system in schizophrenia. One of the most widely distributed receptors in the central nervous system is the glutamatergic N-methyl D-aspartate (NMDA) receptor, responsible for memory and learning. This receptor is highly sensitive to the levels of molecules such as glutamate and D-serine (the endogenous co-agonists of this receptor). According to the glutamatergic hypofunction model of schizophrenia overactivity in Kynurenine Aminotransferase (KAT), which synthesizes kynurenic acid, an NMDA antagonist, may be an important link in brain health.  We are using the three-dimensional structure to design improved inhibitors. Pure KAT-2, obtained by heterologous expression, is required to allow determination of strategic information about the inhibitors interacting with the enzyme, and inhibition assays of the KAT-2 can be performed using HPLC assays.   The methods here represent the basic strategies for the rational design of more potent inhibitors of KAT-2, but in addition are many important variations and specializations of these to increase our chances of continuing our success.

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Keywords

Schizophrenia, Proteins, protein ligand complexes, protein structure, drug design, structure-based drug design, fragment-based drug design, inhibitors, rational drug design, Brain & nervous system disorders

Opportunity ID

The opportunity ID for this research opportunity is: 2823

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