OPTIMIZING THE BINDING OF FULLERENE INHIBITORS OF THE HIV-1 PROTEASE THROUGH PREDICTED INCREASES IN HYDROPHOBIC DESOLVATION

We have developed and applied a computational strategy to increase the affinity of fullerene-based inhibitors of the HIV protease. The resul t is a similar to 50-fold increase in affinity from previously tested fullerene compounds. The strategy is based on the design of derivative s which may potentially increase hydrophobic desolvation upon complex formation, followed by the docking of the hypothetical derivatives int o the HIV protease active site and assessment of the model complexes s o formed. The model complexes are generated by the program DOCK and th en analyzed for desolvated hydrophobic surface. The amount of hydropho bic surface desolvated was compared with a previously tested compound, and if this amount was significantly greater, it was selected as a ta rget. Using this approach, two targets were identified and synthesized , using two different synthetic approaches: a diphenyl C-60 alcohol (5 ) based on a cyclopropyl derivative of Bingel (Chem. Ber. 1993, 226, 1 957-1959) and a diisopropyl cyclohexyl C-60 alcohol (4a) as synthesize d by Ganapathi et al. (J. Org. Chem. 1995, 60, 2954-2955). Both showed tighter binding than the originally tested compound (diphenethylamino succinate methano-C-60, K-i = 5 mu M) with K-i values of 103 and 150 n M, respectively. In addition to demonstrating the utility of this appr oach, it shows that simple modification of fullerenes can result in hi gh-affinity ligands of the HIV protease, for which they are highly com plementary in structure and chemical nature.