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 C-2-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, t he simulations show that such a small difference in binding free energ ies is due to (1) weaker hydrogen bond interactions between the two (P -1 and P-1') NH groups of A-74704 with Gly27/Gly27' carbonyls of the e nzyme and (2) the higher desolvation free energy of A-74704 compared w ith its ester analog. The results of these calculations and their impl ications for design of HIV-1 protease inhibitors are discussed.