Abstract
The Human Immunodeficiency Virus type 1 protease enzyme (HIV-1 PR) is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients. The success of protease-inhibitors (PIs), however, is often limited by the emergence of protease mutations that can confer resistance to a specific drug, or even to multiple PIs. In the present study, we used bioinformatics tools to evaluate the impact of the unusual mutations D30V and V32E over the dynamics of the PR-Nelfinavir complex, considering that codons involved in these mutations were previously related to major drug resistance to Nelfinavir. Both studied mutations presented structural features that indicate resistance to Nelfinavir, each one with a different impact over the interaction with the drug. The D30V mutation triggered a subtle change in the PR structure, which was also observed for the well-known Nelfinavir resistance mutation D30N, while the V32E exchange presented a much more dramatic impact over the PR flap dynamics. Moreover, our in silico approach was also able to describe different binding modes of the drug when bound to different proteases, identifying specific features of HIV-1 subtype B and subtype C proteases.
Highlights
Human immunodeficiency virus type 1 protease (HIV-1 PR) is a catalytic protein that cleaves the Gag and Gag-Pol viral polyproteins, allowing the virus to efficiently infect new host cells
No evident differences were observed in the Root Mean Square Deviation (RMSD) among all five replicated simulations of subtype B wild-type (sB-WT), subtype B (sB)-D30N and Subtype B D30V (sB-D30V) (Figure 1 and Figure S2)
Extension of selected complexes up to 50 ns In order to verify if the differences observed among the complexes were not influenced by the short period of simulation, we extended one of each simulation from the proteases that remained in a closed conformation in the first 10 ns
Summary
Human immunodeficiency virus type 1 protease (HIV-1 PR) is a catalytic protein that cleaves the Gag and Gag-Pol viral polyproteins, allowing the virus to efficiently infect new host cells. The HIV-1 protease is one of the most important targets of antiretroviral therapy used in the treatment of AIDS patients due to its critical role in the viral replication cycle. Protease inhibitors (PI) were developed to inhibit cleavage function of HIV-1 protease by mimicking the reaction intermediates that arises during the hydrolysis of the substrate, disabling the enzyme. The current success of PIs is frequently limited by the emergence of protease gene mutations that confer resistance to this drug class. By changing the structure of the substrate-binding cavity, mutations directly or indirectly interfere with the binding of inhibitors, resulting in viral resistance to PIs
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