Modeling of HIV protease reactivity and interactions with amino-aldehyde inhibitors

This Phd manuscript deals with the modeling of the HIV-1 protease (HIV-1 PR), using a variety of computational chemistry methods. Two specific models have been developed. The first one corresponds to the active site of the enzyme in complex with the substrate. A comparative study based on several theoretical methods enables to show that the hybrid approach QM/MM-BLYP/PW:AMBER is a very good compromise between accuracy and computational cost. The second model represents a complex between the protein and an amino-aldehyde inhibitor, described at the QM/MM-BLYP/PW:AMBER level. Our calculations highlight some destabilizing interactions between the enzyme and the inhibitor. These results suggest the development of alternative amino-aldehyde inhibitors that may provide an enhanced affinity with HIV-1PR.LYON-ENS Sciences (693872304) / SudocSudocFranceF