Abstract
This chapter focuses on the structure-based design strategies employed to inhibit the HIV protease. The design strategy takes two general forms: (1) determination of crystal structures of complexes between the protease and compounds with known inhibitory potency to define characteristics leading to efficient binding and (2) theoretical approaches using the known crystal structure of the protease to predict structures of inhibitory compounds followed by experimental verification. It is difficult to find patterns that lead obviously to high affinity if the peptide-based HIV protease inhibitors are considered. The general principle that increasing the hydrophobicity of the inhibitor leads to tighter binding seems to be established, but the question of the role of symmetry remains unresolved. Putative transition state analogs are effective inhibitors because they add at least one strong hydrogen bond but studies of these compounds have not established the mechanism of the enzyme nor have they confirmed the hypothesis that their tight binding results from their resemblance to the activated complex.