2. Academic Validation
  3. Discovery of a Noncompetitive Open-Flap Selective Inhibitor of Plasmepsin II with Antiplasmodial Activity

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

  • J Chem Inf Model. 2025 Feb 24;65(4):2038-2051. doi: 10.1021/acs.jcim.4c02059.
Pedro A Valiente 1,  Yasel Guerra 2 3,  Maarten G Wolf 4,  Isel Pascual 1,  Enrique Rudiño-Piñera 5,  Isabelle Florent 6,  Tirso Pons 7,  Gerrit Groenhof 4 8
Affiliations

Affiliations

  • 1 Centro 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.
  • 2 Grupo de Bio-Quimioinformática, Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Campus UDLAPARK, Vía a Nayón, Quito 170124, Ecuador.
  • 3 Ingeniería en Biotecnología, Facultad de Ingeniería y Ciencias Aplicadas, Universidad de Las Américas, Campus UDLAPARK, Vía a Nayón, Quito 170124, Ecuador.
  • 4 Biomolecular Chemistry Group, Theoretical and Computational Biophysics Department, Max Planck Institute for Multidisciplinary Sciences (Faßberg-Campus), Am Faßberg 11, 37077 Göttingen, Germany.
  • 5 Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, UNAM, Av. Universidad 2001, Chamilpa, 62210 Cuernavaca, Morelos, México.
  • 6 Département Adaptations du Vivant (AVIV), Molécules de Communication et Adaptation des Microorganismes (MCAM, UMR 7245 CNRS), Muséum National d'Histoire Naturelle (MNHN), CP 52, 57 rue Cuvier, 75231 Cedex 05 Paris, France.
  • 7 Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C. de Melchor Fernández Almagro, 3, Fuencarral-El Pardo, 28029 Madrid, Spain.
  • 8 Department of Chemistry and NanoScience Center, University of Jyvaskyla, Survontie 9c, 40500 Jyvaskyla, Finland.
PMID: 39915939 DOI: 10.1021/acs.jcim.4c02059
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).

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