2025

Valiente, Pedro A.; Guerra, Yasel; Wolf, Maarten G.; Pascual, Isel; Rudiño-Piñera, Enrique; Florent, Isabelle; Pons, Tirso; Groenhof, Gerrit

Here, we predicted that Plasmepsin II (PlmII) can explore open-flap conformations not sampled for human aspartic proteases: Cathepsin D, Renin, and Pepsin were used in molecular dynamics simulations. We combined 24 independent (50 ns) MD runs to improve the conformational sampling of each system. We discovered two PlmII noncompetitive selective inhibitors: SPB07935 and RH01201, with Ki values in the μM range by targeting the open-flap conformations. Both compounds did not inhibit 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 semiopen 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 (CC50 = 189 μM).