INHIBITION OF THE HIV-1 PROTEASE BY FULLERENE DERIVATIVES - MODEL-BUILDING STUDIES AND EXPERIMENTAL-VERIFICATION

The ability of C60 fullerene (''Bucky Ball'') derivatives to interact with the active site of HIV-1 protease (HIVP) has been examined throug h model building and simple physical chemical analysis. The model comp lexes generated via the program DOCK3 suggest that C60 derivatives wil l fit snugly in the active site, thereby removing 298 angstrom2 of pri marily nonpolar surface from solvent exposure and driving ligand/prote in association. The prediction that these compounds should bind to the active site and thereby act as inhibitors has been borne out by the e xperimental evidence. Kinetic analysis of HIVP in the presence of a wa ter-soluble C60 derivative, bis(phenethylamino-succinate) C60, suggest s a competitive mode of inhibition. This is consistent with and suppor ts the predicted binding mode. Diamino C60 has been proposed as a ''se cond-generation'' C60 derivative that will be able to form salt bridge s with the catalytic aspartic acids in addition to van der Waals conta cts with the nonpolar HIVP surface, thereby improving the binding rela tive to the tested compound.