Computer-assisted design of new drugs based on retrometabolic concepts.

Retrometabolic drug design approaches incorporate metabolic and toxicological considerations into the drug design process and represent a novel, systematic methodology for the design of safe compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on isosteric-isoelectronic comparisons, predicted solubility/partition properties, and estimated metabolic rates. The novel field of large peptide-CDSs imposes special challenges, but a new, remarkably simple model was developed to estimate partition properties for a wide range of compounds, including quite large peptide derivatives. A suggested change of about five order of magnitudes in the distribution coefficient can explain the "lock in" mechanism of brain-targeting delivery systems.