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Discovery of a Noncompetitive Open-Flap Selective Inhibitor of Plasmepsin II with Antiplasmodial Activity
Pedro A Valiente1, Yasel Guerra2,3, Maarten G Wolf4
1Centro de Estudios de Proteínas (CEP), Facultad de Biología, Universidad de La Habana, Calle 25 #455% J e I, Plaza de la Revolución, CP 10400 La Habana, Cuba.
Abstract:
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).
Insights
New inhibitors targeting Plasmepsin II (PlmII) open-flap conformations were discovered. SPB07935 effectively inhibited Plasmodium falciparum growth while showing low toxicity to human cells.
Area of Science:
- Biochemistry
- Structural Biology
- Parasitology
Background:
- Plasmepsin II (PlmII) is a key aspartic protease in Plasmodium falciparum.
- Understanding PlmII's unique conformational dynamics, particularly open-flap states, is crucial for developing selective inhibitors.
- Human aspartic proteases like Cathepsin D, Renin, and Pepsin exhibit different conformational preferences.
Purpose of the Study:
- To investigate the conformational landscape of Plasmepsin II using molecular dynamics simulations.
- To identify and characterize novel selective inhibitors targeting PlmII's open-flap conformations.
- To evaluate the antimalarial activity and cellular toxicity of identified inhibitors.
Main Methods:
- Extensive molecular dynamics (MD) simulations (24 x 50 ns runs) were employed to enhance conformational sampling of Plasmepsin II.
- In silico screening and characterization of PlmII inhibitors, SPB07935 and RH01201, focusing on their binding to open-flap states.
- In vitro assays to determine inhibitor selectivity against human Cathepsin D (hCatD), antimalarial activity against Plasmodium falciparum, and cytotoxicity against HEK-293 human cells.
Main Results:
- Plasmepsin II was predicted to explore open-flap conformations distinct from human aspartic proteases.
- Two noncompetitive selective inhibitors, SPB07935 and RH01201, were identified with micromolar (μM) Ki values.
- SPB07935 demonstrated potent inhibition of chloroquine-resistant Plasmodium falciparum growth (IC50 = 8 μM) with significantly lower toxicity to human cells (CC50 = 189 μM).
Conclusions:
- Plasmepsin II's ability to adopt open-flap conformations presents a viable target for drug development.
- SPB07935 and RH01201 represent promising lead compounds for antimalarial therapies due to their selectivity and efficacy.
- The identified inhibitors stabilize PlmII's unique conformations, offering a novel strategy against malaria.
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