Abstract:Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here we explore the selectivity determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors, and describe the critical transition states in atomistic resolution. The simulation results are compared to experimentally determined enzymatic activities. Our finding… Show more
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