Computer-Aided Design of New Drugs Based on Retrometabolic Concepts
Nicholas Bodor, Ming‐Ju Huang · ACS symposium series · 1995
Traditional methods of drug design have relied on maximization of drug activity, which, however, often produce highly potent derivatives with equally elevated toxicities, resulting in no change in the therapeutic index. Inclusion of metabolic and toxicological considerations in the drug design process is embodied in retrometabolic concepts. This systemic methodology employs several rules for design of safe drugs, either by metabolic activation (chemical delivery systems) or strategic enzymatic deactivation processes (soft drugs). Automation of these drug design processes was accomplished by artificial intelligence-based computer programs. Thus, new structures are generated from any lead compound, using the "soft analog" and the "inactive metabolite" approach strategies. All structures are conformationally optimized. Then they are ranked based on calculated properties: solubility and partition characteristics, isosteric-isoelectronic comparison to the lead, and estimated metabolic rates of the predicted enzymatic degradation.