Abstract: AIM: Studies of small nonpeptidic HIV protease inhibitors based on the 3D structure of the active site of the enzyme. METHODS: Docking algorithm of computer-aided molecular design as described in this paper. It is a cycle, consisting of molecular building, energy minimization, auto-docking and evaluation of interaction energy, according to the correlation reported lately between the observed in vitro enzyme inhibition and the interaction energy. RESULTS: The series of nonpeptidic small compounds have been modeled and optimized in the binding cavity of HIV protease. Most of the designed molecules in this paper are predicted that they not only inhibit the enzyme, but also have high specificity due to the simulation of bound water. In addition, they seem to have better oral bioavailability for lack of peptide nature. CONCLUSION: Small nonpeptidic molecules are expected to become HIV protease inhibitors with high activity, specificity and good oral bioavailability.