SOLVENT ACCESSIBILITY AS A PREDICTIVE TOOL FOR THE FREE-ENERGY OF INHIBITOR BINDING TO THE HIV-1 PROTEASE

We have developed a simple approach for the evaluation of the free ene rgies of inhibitor binding to the protease of the human immunodeficien cy virus (HIV-1 PR). Our algorithm is based on the observation that mo st groups that line the binding pockets of this enzyme are hydrophobic in nature. Based on this fact, we have likened the binding of an inhi bitor to this enzyme to its transfer from water to a medium of lower p olarity. The resulting expression produced values for the free energy of binding of inhibitors to the HIV-1 PR that are in good agreement wi th experimental values. The additive nature of this approach has enabl ed us to partition the free energy of binding into the contributions o f single fragments. The resulting analysis clearly indicates the exist ence of a ranking in the participation of the enzyme's subsites in bin ding. Although all the enzyme's pockets contribute to binding, the one s that bind the P-2-P-2' span of the inhibitor are in general the most critical for high inhibitor potency. Moreover, our method has allowed us to determine the nature of the functional groups that fit into giv en enzyme binding pockets. Perusal of the energy contributions of sing le side chains has shown that a large number of hydrophobic and aromat ic groups located in the central portion of the HIV-1 PR inhibitors pr esent optimal binding. All of these observations are in agreement with experimental evidence, providing a validation for the physical releva ncy of our model.