Irreversible inhibition of the HIV-1 protease: A theoretical study

Reaction coordinate for the irreversible inhibition of the HIV-1 protease by epoxy alkylating agent has been examined by ab initio HF/6-31G(d) calculations, semiempirical molecular orbital (MO) calculations, while the effect of polar macromolecular environment was included on the solvent reaction field level. The calculations, show that inhibition is specific: activation (free) energy is low when two carboxylic groups that are models for Asp-25 and Asp-125 in the HIV-1 protease active center are involved and is considerably higher when only one formate or CH3S- is present. The latter two mimick any single carboxylate side chain and cysteine side chain, respectively. inclusion of solvent reaction field slightly changes the activation free energy. The calculations confirm experimental data concerning the necessity of two-aspartate motif of the protease active center to activate the alkylating agent [Yu et al., J. Am. Chem. Sec. 118, 5856 (1996)]. The results are discussed in the context of design of nonirreversible inhibitors. (C) 1998 John Wiley & Sons, Inc.