Computer Modeling of Enzyme Catalysis and Inhibition

Computer modeling techniques have been extensively
used to aid drug design via enzymatic reaction
studies. Here we present the investigations of the
catalysis by orotidine monophosphate decarboxylase
(ODCase) and the inhibition of protein kinase C
(PKC) isozymes. Decarboxylation, pseudohydrolysis
and covalent inhibition reactions were studied using
QM and QM/MM methods to understand the mechanistic
details of ODCase catalysis. The catalytic site
architecture and binding interactions of PKC
isozymes , and were also investigated in the
context of PKC- inhibitor, ruboxistaurin. Homology
modeling and docking techniques were used to model
the three-dimensional structures of the kinase
domains of PKC isozymes and the PKC-ruboxistaurin
complexes. For the first time, specific interactions
for ruboxistaurin that favor binding to PKC- were
uncovered. Our study provides opportunity to design
isozyme-specific inhibitors for PKC.

Autorentext

Sishi Tang is a Ph.D candidiate in computational biophysics at the Scripps Research Institute in La Jolla, CA. She completed her Master's degree in pharmaceutical sciences at University of Toronto, Canada.

Klappentext

Computer modeling techniques have been extensively used to aid drug design via enzymatic reaction studies. Here we present the investigations of the catalysis by orotidine monophosphate decarboxylase (ODCase) and the inhibition of protein kinase C (PKC) isozymes. Decarboxylation, pseudohydrolysis and covalent inhibition reactions were studied using QM and QM/MM methods to understand the mechanistic details of ODCase catalysis. The catalytic site architecture and binding interactions of PKC isozymes a, ß and were also investigated in the context of PKC-ß inhibitor, ruboxistaurin. Homology modeling and docking techniques were used to model the three-dimensional structures of the kinase domains of PKC isozymes and the PKC-ruboxistaurin complexes. For the first time, specific interactions for ruboxistaurin that favor binding to PKC-ß were uncovered. Our study provides opportunity to design isozyme-specific inhibitors for PKC.