Abstract
Strong hydrogen-bonding forces between the Thr26 and Thr26′of the protease stabilize the internal cage of the dimeric triad of the aspartyl HIV-1 protease (Asp25Thr26Gly27 and Asp25′Thr26′Gly27′, respectively). The interaction of reversible inhibitors of HIV-1 protease is based on (i) strong hydrogen-bonding forces between the main chain (─CONH─) oxygen atoms of Gly27 and/or Gly27′and hydrogen-bond donating moieties of a drug, and (ii) hydrogen bonds between the oxygen of the catalytic Asp25 and/or Asp25′carboxylates and aliphatic hydroxyl groups of a drug. The free entry of natural substrates into the active-site cavity is sterically hindered by inhibitors, so that the catalytic Asp carboxylates cannot interact with natural substrates. Irreversible inhibitors interact with the nucleophilic carboxylate moiety of Asp25 of HIV-1 protease by covalent bonding.