Homology Modeling of Human Kynurenine Aminotransferase III and Observations on Inhibitor Binding Using Molecular Docking
Alireza Nematollahi, William B. Church, Naveed A. Nadvi, Mark D. Gorrell and Guanchen Sun
Affiliation: Faculty of Pharmacy A15, The University of Sydney, Sydney NSW 2006, Australia.
Keywords: Docking, homology modeling, kynurenine aminotransferase, molecular dynamics simulation, schizophrenia.
Kynurenine aminotransferase (KAT) isozymes are responsible for catalyzing the conversion of kynurenine
(KYN) to kynurenic acid (KYNA), which is considered to play a key role in central nervous system (CNS) disorders,
including schizophrenia. The levels of KYNA in the postmortem prefrontal cortex and in the Cerebrospinal fluid (CSF) of
schizophrenics are greater than normal brain. A basic strategy to decrease kynurenic acid levels is to promote the
inhibition of the biosynthetic KAT isozymes. As there is no crystallographic model for human kynurenine
aminotransferase III (KAT III), therefore, homology modeling has been performed based on the Mus musculus kynurenine
aminotransferase III crystal structure (PDB ID: 3E2Y) as a template, and the model of the human KAT III was refined and
optimized with molecular dynamics simulations. Further evaluation of the model quality was accomplished by
investigating the interaction of KAT III inhibitors with the modeled enzyme. Such interactions were determined
employing the AutoDock 4.2 program using the MGLTools 1.5.6 package. The most important interactions for the
binding of the inhibitors, which are probably also central components of the active site of KAT III, were identified as
Ala134, Tyr135, Lys 280, Lys 288, Thr285 and Arg429, which provide hydrogen bond interactions. Additionally, Tyr135
and Arg429 have good electrostatic interactions with inhibitors consistent with these residues also being essential for
inhibition of the enzyme activity. We expect that this model and these docking data will be a useful resource for the
rational design of novel drugs for treating neuropathologies.
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