The future of prodrugs - design by quantum mechanics methods

The revolution in computational chemistry greatly impacted the drug design and delivery fields, in general, and recently the utilization of the prodrug approach in particular. The use of ab initio, semiempirical and molecular mechanics methods to understand organic reaction mechanisms of certain processes, especially intramolecular reactions, has opened the door to design and to rapidly produce safe and efficacious delivery of a wide range of active small molecule and biotherapeutics such as prodrugs.

This article provides the readers with a concise overview of this modern approach to prodrug design. The use of computational approaches, such as density functional theory (DFT), semiempirical and ab initio molecular orbital methods, in modern prodrugs design will be discussed. The novel prodrug approach to be reported in this review implies prodrug design based on enzyme model (mimicking enzyme catalysis) that has been utilized to understand how enzymes work. The tool used in the design is a computational approach consisting of calculations using molecular orbital and molecular mechanics methods (DFT, ab initio and MM2) and correlations between experimental and calculated values of intramolecular processes that were used to understand the mechanism by which enzymes might exert their high rates catalysis.

The future of prodrug technology is exciting yet extremely challenging. Advances must be made in understanding the chemistry of many organic reactions that can be effectively utilized to enable the development of even more types of prodrugs. Despite the increase in the number of marketed prodrugs, we have only started to appreciate the potential of the prodrug approach in modern drug development, and the coming years will witness many novel prodrug innovations.