ArticleActa crystallographica. Section F, Structural biology communications2015
Structures of plasmepsin II from Plasmodium falciparum in complex with two hydroxyethylamine-based inhibitors.
Article in Acta crystallographica. Section F, Structural biology communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 21 citations in OpenAlex.
- Aspartyl protease inhibition interferes with Plasmodium falciparum asexual blood-stage and early gametocyte development.Malaria journal · 2025Article
- Computational analysis of luteolin, apigenin and their derivatives from Allophylus africanus as potential inhibitors of plasmepsin II a malaria target.BMC chemistry · 2025Article
- Inhibition ofCurrent research in structural biology · 2024Article
- In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity.Parasitology research · 2023Article
- Accelerating Cryptic Pocket Discovery Using AlphaFold.Journal of chemical theory and computation · 2023Article
- The Multistage Antimalarial Compound Calxinin PerturbatesPharmaceutics · 2022Article
- Flap Dynamics in Pepsin-Like Aspartic Proteases: A Computational Perspective Using Plasmepsin-II and BACE-1 as Model Systems.Journal of chemical information and modeling · 2022Article
- Pepsin-like aspartic proteases (PAPs) as model systems for combining biomolecular simulation with biophysical experiments.RSC advances · 2021Review
- Deciphering the mechanism of potent peptidomimetic inhibitors targeting plasmepsins - biochemical and structural insights.The FEBS journal · 2018Article
- Modeling and resistant alleles explain the selectivity of antimalarial compound 49c towards apicomplexan aspartyl proteases.The EMBO journal · 2018Article
- A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress.Science (New York, N.Y.) · 2017Article
- Crystal structure of Plasmodium falciparum proplasmepsin IV: the plasticity of proplasmepsins.Acta crystallographica. Section F, Structural biology communications · 2016Article
- Evaluation of Antimalarial Activity of Ethanolic Extract ofJournal of evidence-based integrative medicineArticle
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Plasmepsin II (PMII) is one of the ten plasmepsins (PMs) identified in the genome of Plasmodium falciparum, the causative agent of the most severe and deadliest form of malaria. Owing to the emergence of P. falciparum strains that are resistant to current antimalarial agents such as chloroquine and sulfadoxine/pyrimethamine, there is a constant pressure to find new and lasting chemotherapeutic drug therapies. Previously, the crystal structure of PMII in complex with NU655, a potent antimalarial hydroxyethylamine-based inhibitor, and the design of new compounds based on it have been reported. In the current study, two of these newly designed hydroxyethylamine-based inhibitors, PG418 and PG394, were cocrystallized with PMII and their structures were solved, analyzed and compared with that of the PMII-NU655 complex. Structural analysis of the PMII-PG418 complex revealed that the flap loop can adopt a fully closed conformation, stabilized by interactions with the inhibitor, and a fully open conformation, causing an overall expansion in the active-site cavity, which in turn causes unstable binding of the inhibitor. PG418 also stabilizes the flexible loop Gln275-Met286 of another monomer in the asymmetric unit of PMII, which is disordered in the PMII-NU655 complex structure. The crystal structure of PMII in complex with the inhibitor PG418 demonstrates the conformational flexibility of the active-site cavity of the plasmepsins. The interactions of the different moieties in the P1' position of PG418 and PG394 with Thr217 have to be taken into account in the design of new potent plasmepsin inhibitors.
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