Computer-aided retrometabolic drug design: soft drugs

Soft drug design approaches aim to design new therapeutic agents that undergo facile, preferentially hydrolytic metabolism to produce inactive metabolites. This approach is general and can be used in essentially any therapeutic area, especially where the desired activity is localized, relatively short-lived or susceptible to easy titration. In most cases, this approach aims to design close steric and electronic analogs of an existing drug, which serves as a lead for the design. Therefore, computer programs that can generate virtual libraries of possible analogs and can provide quantitative tools to rank them on the basis of the closeness of their properties to the original lead are of particular relevance. Related aspects, including quantitative structure-metabolism relationships tools to predict hydrolytic stability are reviewed together with illustrative examples.