COMPUTER-ASSISTED DESIGN OF NEW DRUGS BASED ON RETROMETABOLIC CONCEPTS

Retrometabolic drug design approaches incorporate metabolic and toxico logical considerations into the drug design process and represent a no vel, systematic methodology for the design of safe compounds. Two majo r design concepts aimed to increase the therapeutic index (the activit y/toxicity ratio) of drugs were developed. Chemical delivery systems ( CDS) are primarily used to allow targeting of the active biological mo lecules to specific target sites or organs based on predictable enzyma tic activation. Sofi drug approaches are used to design new drugs by b uilding in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequ ent to exerting its biological effects. Special computer programs were developed that starting from a lead compound generate complete librar ies of possible soft analogs and then help ranking these candidates ba sed on isosteric-isoelectronic comparisons, predicted solubility/parti tion properties, and estimated metabolic rates. The novel field of lar ge peptide-CDSs imposes special challenges, but a new, remarkably simp le model was developed to estimate partition properties for a wide ran ge of compounds, including quite large peptide derivatives. A suggeste d change of about five order of magnitudes in the distribution coeffic ient can explain the ''lock in'' mechanism of brain-targeting delivery systems.