Our search for novel scaffolds with improved pharmacokinetic properties5c,g has led to several potent pyrrolinone-based inhibitors of HIV-1 protease. These monopyrrolinones are completely stable to proteases, and 6 proved to be orally bioavailable in dogs. Cocrystallization of 6 with the enzyme and X-ray analysis revealed an unexpected hydrogen bond between Asp25 and the pyrrolinone NH as well as the incorporation of a water molecule linking the indane hydroxyl and the NH of Asp29. The protease complexes of pyrrolinone 6 and Crixivan both crystallize in a single orientation. Notwithstanding the overall similarity of the latter structures, significant differences in the conformation and H-bonding of the enzyme are discernible both in the active site and in other regions. We believe that if the concept of single-mechanism cocktails3 of HIV-1 protease inhibitors is eventually validated in the clinic, its benefits can be optimized by maximizing the structural diversity of the protease inhibitors comprising the cocktail. We are currently synthesizing several pyrrolinones designed to provide higher affinity by preventing the entropically unfavorable binding of water in the active site while maintaining the H-bond to Asp25.