De novo drug design of a new copper chelate molecule acting as HIV-1 protease inhibitor

An original pharmacophore for the active site of the HIV-1 protease was built based on the presence of a catalytic water molecule found between the two catalytic residues Asp25 and Asp125. Using this pharmacophore, a screening of metallo-organic complexes was performed based on the fact that such metallic compounds are known to inhibit the enzyme activity. We observed that diaqua[bis-(2-pyridylcarbonyl)-amido] copper (II) nitrate dihydrate fitted in the active site of the enzyme. Experimentally. it was found to be a competitive inhibitor of the protease (K-i = 480 +/- 120 mu M). The de novo discovery of this novel HIV-1 protease inhibitor stressed the fact that the catalytic water molecule has to be taken into consideration for the design of non-peptide inhibitors of the protease. (C) Elsevier, Paris.