Density Functional Theory (DFT) and ab initio calculation results for the proton transfer reaction in Kirby’s enzyme models 1-6 reveal that the reaction rate is largely dependent on the existence of a hydrogen bonding net in the reactants and the corresponding transition states. Further, the distance between the two reacting centers and the angle of the hydrogen bonding formed along the reaction path has profound effects on the rate. Hence, the study on the systems reported herein could provide a good basis for designing antimalarial (atovaquone) pro-drug systems that can be used to release the parent drug in a controlled manner. For example, based on the calculated log EM, the cleavage process for pro-drug 1Pro may be predicted to be about 1011 times faster than that for a pro-drug 4Pro and about 104 times faster than pro-drug 2Pro: rate 1Pro > rate 2Pro > rate 4Pro. Thus, the rate by which the pro-drug releases the antimalarial drug can be determined according to the nature of the linker (Kirby’s enzyme model 1-6).