The striking efficiency of enzyme catalysis has 
inspired many organic chemists to explore enzyme 
mechanism(s) by studying certain intramolecular processes 
(enzyme models) which proceed faster than their 
intermolecular counterparts. This editorial describes the 
use of computational methods such as quantum mechanics 
and molecular mechanics to explore the mechanisms of 
various enzyme models for assigning the factors affecting 
the rate-limiting step and determining the mode and action 
of the reaction. Among the enzyme models discussed 
herein are: (a) proton transfer between two oxygen atoms 
and proton transfer between nitrogen and oxygen in 
Kirby’s enzyme model; (b) intramolecular acid-catalyzed 
hydrolysis in some of Kirby’s N-alkylmaleamic acids; (c) 
proton transfer between two oxygen atoms in Menger’s 
rigid system; (d) acid-catalyzed lactonization of hydroxy
acids as studied by Cohen and (e) SN2-based cyclization 
as studied by Bruice. These enzyme models were utilized 
as linkers to be covalently attached to commonly used 
drugs having poor bioavailability or/and bitter sensation. 
The conversion rate of the prodrug to its active form is 
solely determined on the structural features of the linker