ArticleJournal of chemical information and modeling2022
Exploring the pH- and Ligand-Dependent Flap Dynamics of Malarial Plasmepsin II.
Article in Journal of chemical information and modeling, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
6 citing papers in PubMed, 10 citations in OpenAlex.
- Conformational Dynamics of Plasmepsin X during Inhibitor Binding.The journal of physical chemistry. B · 2026Article
- Permeation enhancer-induced membrane defects assist the oral absorption of peptide drugs.Nature communications · 2025Article
- Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X inRSC chemical biology · 2024Article
- PKAD-2: New entries and expansion of functionalities of the database of experimentally measured pKa's of proteins.Journal of computational biophysics and chemistry · 2023Article
- Constant pH molecular dynamics simulations: Current status and recent applications.Current opinion in structural biology · 2022Review
- A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].Living journal of computational molecular science · 2022Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Malaria remains a global health threat─over 400,000 deaths occurred in 2019. Plasmepsins are promising targets of antimalarial therapeutics; however, no inhibitors have reached the clinic. To fuel the progress, a detailed understanding of the pH- and ligand-dependent conformational dynamics of plasmepsins is needed. Here we present the continuous constant pH molecular dynamics study of the prototypical plasmepsin II and its complexed form with a substrate analogue. The simulations revealed that the catalytic dyads D34 and D214 are highly coupled in the apo protein and that the pepstatin binding enhances the difference in proton affinity, making D34 the general base and D214 the general acid. The simulations showed that the flap adopts an open state regardless of pH; however, upon pepstatin binding the flap can close or open depending on the protonation state of D214. These and other data are discussed and compared with the off-targets human cathepsin D and renin. This study lays the groundwork for a systematic investigation of pH- and ligand-modulated dynamics of the entire family of plasmepsins to help design more potent and selective inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.