title: Improving the passive permeability of macrocyclic peptides: Balancing permeability with other physicochemical properties.
abstract: 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.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Praew
authors.initials: P
authors.lastname: Thansandote
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Harris
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Dexter
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Electronic address: graham.l.simpson@gsk.com.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Simpson
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pal
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Upton
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Klara
authors.initials: K
authors.lastname: Valko
mesh_terms: D006860:Hydrogen Bonding; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism*; D010539:Permeability; D017434:Protein Structure, Tertiary; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D010456:Peptides, Cyclic
keywords: Macrocyclic peptides; Medicinal chemistry; Passive permeability; Physicochemical properties; Protein–protein interactions; Therapeutic peptides