Free energy perturbation studies on binding of A-74704 and its diester analog to HIV-1 protease

Free energy simulations have been employed to rationalize the binding differences between A-74704, a pseudo C2-symmetric inhibitor of HIV-1 Protease and its diester analog. The diester analog inhibitor, which misses two hydrogen bonds with the Enzyme active site, is surprisingly only 10-fold weaker. The calculated free energy difference of 1.7 +/- 0.6 kcal/mol is in agreement with the experimental result. Further, the simulations show that such a small difference in binding free energies is due to (1) weaker hydrogen bond interactions between the two (P1 and P1') NH groups of A-74704 with Gly27/Gly27' carbonyls of the Enzyme and (2) the higher desolvation free energy of A-74704 compared with its ester analog. The results of these calculations and their implications for design of HIV-1 Protease Inhibitors are discussed.