Discovery of a Non-Competitive Open-Flap Selective Inhibitor of Plasmepsin II with Antiplasmodial Activity

Here, we predicted that Plasmepsin II (PlmII) can explore open-flap conformations not sampled for the human aspartic proteases: Cathepsin D, Renin, and Pepsin along µs molecular dynamics simulations. We discovered two PlmII non-competitive selective inhibitors: SPB07935 and RH01201, with Ki values in the µM range by targeting the open-flap conformations. Both compounds did not inhibit the human Cathepsin D (hCatD) at high concentrations. We predicted that SPB07935 and RH01201 bind stably to the flap cryptic pocket, keeping this hairpin in an open or semi-open conformation along the MD simulations, respectively. Significantly, SPB07935 inhibited the P. falciparum chloroquine-resistant strain FcB1 growth in vitro, with an IC50 value of 8 µM while having a lower toxicity for HEK-293 human cells (IC50 = 189 µM).