DFT calculations at B3LYP/6-31G(d,p) for intramolecular proton transfer in Kirby's enzyme models 1-7 demonstrated that the reaction rate is dependent on the distance between the two reacting centers, rGM, and the hydrogen bonding angle, α, and the rate of the reaction is linearly correlated with rGM and α. Based on these calculation results three simvastatin prodrugs were designed with the potential to provide simvastatin with higher bioavailability. For example, based on the calculated log EM for the three proposed prodrugs, the interconversion of simvastatin prodrug ProD 3 to simvastatin is predicted to be about 10 times faster than that of either simvastatin prodrug ProD 1 or simvastatin ProD 2. Hence, the rate by which the prodrug releases the statin drug can be determined according to the structural features of the promoiety (Kirby's enzyme model).