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 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.