The mechanism of action and mode of inhibition of dihydroorotate dehydrogenase. A quantum chemical study.

Semiemperical quantum chemical calculations have been applied to study the reaction mechanism and mode of inhibition of dihydroorotate dehydrogenase. The structure of substrate, intermediate, product and various inhibitors of dihydroorotate dehydrogenase were optimized using MNDO method and the geometry, heat of formation and the net atomic partial charges of optimized molecules, as well as the energy of the reaction path were calculated. This study shows that the carbanion intermediate of this reaction is rather stable (heat of formation = -134.5 kcal) and readily forms upon nucleophilic attack by groups such as hydroxyl ion. There is good correlation between electronic properties and the biological activities of various inhibitors of this enzyme and the geometry of the most active inhibitor resembles closely that of the intermediate of the reaction. Therefore, it is concluded that the enzymatic oxidation of dihydroorotate dehydrogenase proceeds via formation of an intermediate and the inhibitors bind to the active site of this enzyme in the place of this intermediate.