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netLibrary - eBook Summary Structure-based Drug Design by ...

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Figure 9<br />

The energy profile (as calculated at the 3-21G/PM3 level [24]) for the proton<br />

transfer step A rarrow.gif B and the methyl transfer step B rarrow.gif C for catechol as a<br />

substrate.<br />

Page 351<br />

The pK a of the catecholic hydroxyl is about 9.8. The role of the Mg 2+ ion bound to the enzyme is to<br />

make the hydroxyl groups more easily ionizable. It has been shown <strong>by</strong> quantum mechanical calculations<br />

that the hydroxyl protons can be transferred to Lys144 and Glu199 [24]. The proton transfer OH<br />

rarrow.gif Lys144 activates the hydroxyl group for the methyl transfer AdoMet rarrow.gif O -. Thus<br />

the reaction coordinate for methylation of catechols <strong>by</strong> COMT consists of a proton transfer from a<br />

hydroxyl group to Lys144 and a subsequent methyl transfer from AdoMet to the hydroxyl group (Figure<br />

9). The Lys144 residue acts as a typical catalytic base in a general base-catalysed SN2-like nucleophilic<br />

substitution reaction [24].<br />

IV. Inhibitors of COMT<br />

A. First-Generation Inhibitors<br />

First generation COMT inhibitors such as pyrogallol, U-0521 (3, 4-dihydroxy-2-methylpropiophenone),<br />

tropolone, and 8-hydroxyquinoline (Figure 10) were<br />

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