DE-NOVO DESIGN OF NONPEPTIDIC HIV-1 PROTEASE INHIBITORS - INCORPORATION OF STRUCTURAL WATER

We describe the de novo structure-based design of C2 symmetric, non-pe ptidic HIV PR inhibitors. Cyclic ureas were chosen as synthetic target s owing to their ability to mimic key interacting elements observed in known HIV PP/inhibitor complexes. The urea carbonyl oxygen serves as a replacement for the buried, structural water that occurs in peptide- based inhibitor complexes. The conformational analysis of the six-memb ered pyrimidone ring suggests that N-substituted derivatives should ex hibit a marked stereochemical preference for binding.