THE ATOM ASSIGNMENT PROBLEM IN AUTOMATED DE-NOVO DRUG DESIGN .5. TESTS FOR ENVELOPE-DIRECTED FRAGMENT PLACEMENT BASED ON MOLECULAR SIMILARITY

The fragment placement method has been successfully extended to the pr oblem of envelope-directed design. The atom assignment paradigm was ba sed on molecular similarity between two molecular structures. A compos ite supersurface is defined to form the surface onto which the molecul ar fields are projected. The assignment process is then determined by using molecular similarity in the objective function to be optimized. In principle, this procedure is closely similar to that outlined in th e previous paper for site-directed design. The rationale has been exte nsively tested on two benzodiazepine antagonists believed to bind to t he same site.