Inhibition of the HIV-1 protease by fullerene derivatives: model building studies and experimental verification

The ability of C sub(60) fullerene ("Bucky Ball") derivatives to interact with the active site of HIV-1 protease (HIVP) has been examined through model building and simple physical chemical analysis. The model complexes generated via the program DOCK3 suggest that C sub(60) derivatives will fit snugly in the active site, thereby removing 298 angstrom super(2) of primarily nonpolar surface from solvent exposure and driving ligand/protein association. The prediction that these compounds should bind to the active site and thereby act as inhibitors has been borne out by the experimental evidence. Kinetic analysis of HIVP in the presence of a water-soluble C sub(60) derivative, bis(phenethylamino-succinate) C sub(60), suggests a competitive mode of inhibition. This is consistent with and supports the predicted binding mode. Diamino C sub(60) has been proposed as a "second-generation" C sub(60) derivative that will be able to form salt bridges with the catalytic aspartic acids in addition to van der Waals contacts with the nonpolar HIVP surface, thereby improving the binding relative to the tested compound.