Berlin 2012 – wissenschaftliches Programm

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BP: Fachverband Biologische Physik

BP 15: Proteins II

BP 15.6: Vortrag

Mittwoch, 28. März 2012, 16:30–16:45, H 1058

Origin of decrease in potency against HIV-2 protease by HIV-1 protease inhibitors — •Parimal Kar and Volker Knecht — Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany

The acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV) type 1 and 2 (HIV-1 and HIV-2). An important target for AIDS treatment is the use of HIV protease (PR) inhibitors preventing the replication of the virus. In this work, the popular molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method has been used to investigate the effectiveness of the HIV-1 PR inhibitors darunavir, GRL-06579A, and GRL-98065 against HIV-2 and HIV-1 protease. The affinity of the inhibitors for both HIV-1 and HIV-2 PR decreases in the order GRL-06579A < darunavir < GRL-98065, in accordance with experimental data. On the other hand, our results show that all these inhibitors bind less strongly to HIV-2 compared to HIV-1 protease, again in agreement with experimental findings. The decrease in binding affinity for HIV-2 relative to HIV-1 PR is found to arise from an increase in the energetic penalty from the desolvation of polar groups (DRV), or a decrease in the size of the electrostatic interactions between the inhibitor and the PR (GRL-06579A and GRL-98065). For GRL-98065, also a decrease in the magnitude of the van der Waals interactions contributes to the reduction in binding affinity. A detailed understanding of the molecular forces governing binding and drug resistance might assist in the design of efficient inhibitors against HIV-2 protease.