In human, catechol-O-methyltransferase (COMT: E.C. 22.214.171.124) is responsible for
metabolism of catechol neurotransmitter and xenobiotics. The main clinical
interest in COMT results from the possibility of using COMT inhibitors as
adjuncts in the therapy of Parkinson's disease (PD) with l-DOPA. COMT is
therefore a target for inhibitor development aiming at PD treatment and has been
submitted to extensive structure-based drug design. Recently reported inhibitors
have nitrocatechol structure that may inhibit oxidative phosphorylation and
uncouple mitochondrial energy production. This work reports the first
crystallographic study of Rat COMT complexed with non-nitrocatechol inhibitor.
Analysis of the structural differences among the previously reported inhibitor
complexes, coumarine-based inhibitor (4-phenyl-7, 8-dihydroxycoumarine: 4PCM)
bound structure provides the explanation for inhibitor binding and can be used
for future inhibitor design.