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Title: Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides
Authors: Li, Jianguo
Kannan, Srinivasaraghavan
Aronica, Pietro
Brown, Christopher J.
Partridge, Anthony W.
Verma, Chandra Shekhar
Keywords: Science::Biological sciences
Issue Date: 2022
Source: Li, J., Kannan, S., Aronica, P., Brown, C. J., Partridge, A. W. & Verma, C. S. (2022). Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides. Journal of Chemical Physics, 156(6), 065101-.
Project: H17/01/a0/010
Journal: Journal of Chemical Physics
Abstract: Cyclic peptides represent a promising class of drug candidates. A significant obstacle limiting their development as therapeutics is the lack of an ability to predict their membrane permeability. We use molecular dynamics simulations to assess the ability of a set of widely used parameters in describing the membrane permeability of a set of model cyclic peptides; the parameters include polar surface area (PSA), the number of hydrogen bonds, and transfer free energy between an aqueous phase and a membrane mimicking phase. These parameters were found to generally correlate with the membrane permeability of the set of cyclic peptides. We propose two new descriptors, the charge reweighted PSA and the non-polar surface area to PSA ratio; both show enhanced correlation with membrane permeability. This inspired us to explore crosslinking of the peptide to reduce the accessible surface area of the backbone polar atoms, and we find that this can indeed result in reductions in the accessible PSA. This gives reason to speculate that crosslinking may result in increased permeability, thus suggesting a new scaffold for the development of cyclic peptides as potential therapeutics.
ISSN: 0021-9606
DOI: 10.1063/5.0078025
Schools: School of Biological Sciences 
Organisations: Bioinformatics Institute, A*STAR
National University of Singapore
Rights: © 2022 Author(s). All rights reserved. This paper was published by AIP Publishing in Journal of Chemical Physics and is made available with permission of Author(s).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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