Structure-based design, synthesis, and in vitro evaluation of bisubstrate inhibitors for catechol O-methyltransferase (COMT)

The enzyme catechol O-methyltransferase (COMT) catalyzes the Me group trans fer from the cofactor S-adenosylmethionine (SAM) to the hydroxy group of ca techol substrates. Potential bisubstrate inhibitors of COMT were developed by structure-based design and synthesized. The compounds were tested for in vitro inhibitory activity against COR-IT obtained from rat liver, and the inhibition kinetics were examined with regard to the binding sites of cofac tor and substrate. One of the designed molecules was found to be a bisubstr ate inhibitor of COMT with an IC50 = 2 mu M. It exhibits competitive kineti cs for the SAM and noncompetitive kinetics for the catechol binding site. U seful structure-activity relationships were established which provide impor tant guidelines for the design of future generations of bisubstrate inhibit ors of COMT.