Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties

[Display omitted] A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not on...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2015-01, Vol.23 (2), p.322-327
Main Authors: Thansandote, Praew, Harris, Robert M., Dexter, Hannah L., Simpson, Graham L., Pal, Sandeep, Upton, Richard J., Valko, Klara
Format: Article
Language:English
Subjects:
Hydrogen Bonding
Macrocyclic peptides
Medicinal chemistry
Passive permeability
Peptides, Cyclic - chemistry
Peptides, Cyclic - metabolism
Permeability
Physicochemical properties
Protein Structure, Tertiary
Protein–protein interactions
Solubility
Stereoisomerism
Therapeutic peptides
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Summary:[Display omitted] A number of methods to improve the passive permeability of a set of cyclic peptides have been investigated using 6- and 7-mer macrocyclic templates. In many cases the peptides were designed by molecular dynamics calculations to evaluate the methods. The aim of this study was not only to improve passive permeability, but also to balance permeability with other physicochemical properties with the goal of understanding and applying the knowledge to develop active cyclic peptides into drug candidates. Evaluation of the methods herein suggest that increasing passive permeability often occurs at the expense of solubility and lipophilicity. Computational methods can be useful when attempting to predict and design features to balance these properties, though limitations were observed.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2014.11.034