Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides
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 descri...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Online Access: | https://hdl.handle.net/10356/161250 |
| _version_ | 1826121127427047424 |
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| author | Li, Jianguo Kannan, Srinivasaraghavan Aronica, Pietro Brown, Christopher J. Partridge, Anthony W. Verma, Chandra Shekhar |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Li, Jianguo Kannan, Srinivasaraghavan Aronica, Pietro Brown, Christopher J. Partridge, Anthony W. Verma, Chandra Shekhar |
| author_sort | Li, Jianguo |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T05:27:39Z |
| format | Journal Article |
| id | ntu-10356/161250 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:27:39Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1612502023-02-28T17:13:43Z Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides Li, Jianguo Kannan, Srinivasaraghavan Aronica, Pietro Brown, Christopher J. Partridge, Anthony W. Verma, Chandra Shekhar School of Biological Sciences Bioinformatics Institute, A*STAR National University of Singapore Science::Biological sciences Cell Membrane Permeability Hydrogen Bonding 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. Agency for Science, Technology and Research (A*STAR) Published version This work was supported by collaborative grants from MSD and A*STAR (Grant Nos. H17/01/a0/010, IAF111213C, and SC16/20-302400). 2022-08-22T07:10:07Z 2022-08-22T07:10:07Z 2022 Journal Article 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-. https://dx.doi.org/10.1063/5.0078025 0021-9606 https://hdl.handle.net/10356/161250 10.1063/5.0078025 35168356 2-s2.0-85124660214 6 156 065101 en H17/01/a0/010 IAF111213C SC16/20-302400 Journal of Chemical Physics © 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). application/pdf |
| spellingShingle | Science::Biological sciences Cell Membrane Permeability Hydrogen Bonding Li, Jianguo Kannan, Srinivasaraghavan Aronica, Pietro Brown, Christopher J. Partridge, Anthony W. Verma, Chandra Shekhar Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title | Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title_full | Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title_fullStr | Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title_full_unstemmed | Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title_short | Molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| title_sort | molecular descriptors suggest stapling as a strategy for optimizing membrane permeability of cyclic peptides |
| topic | Science::Biological sciences Cell Membrane Permeability Hydrogen Bonding |
| url | https://hdl.handle.net/10356/161250 |
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