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

✍ Scribed by Janez Mavri

• Publisher: John Wiley and Sons
• Year: 1998
• Tongue: English
• Weight: 183 KB
• Volume: 69
• Category: Article
• ISSN: 0020-7608
• DOI: 10.1002/(sici)1097-461x(1998)69:6<753::aid-qua6>3.0.co;2-u

✦ Synopsis

Reaction coordinate for the irreversible inhibition of the HIV-1 protease Ž . by epoxy alkylating agent has been examined by ab initio HFr6-31G d calculations, Ž . semiempirical molecular orbital MO calculations, while the effect of polar macromolecular environment was included on the solvent reaction field level. The Ž . 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 CH S y is 3 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 twow aspartate motif of the protease active center to activate the alkylating agent Yu et al., J.