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Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides
Author(s) -
Nielsen Daniel S.,
Lohman RinkJan,
Hoang Huy N.,
Hill Timothy A.,
Jones Alun,
Lucke Andrew J.,
Fairlie David P.
Publication year - 2015
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201500441
Subject(s) - bioavailability , cyclic peptide , flexibility (engineering) , chemistry , rigidity (electromagnetism) , structural rigidity , stereochemistry , pharmacology , biochemistry , medicine , materials science , peptide , mathematics , statistics , geometry , composite material
Cyclic peptides and macrocycles have the potential to be membrane permeable and orally bioavailable, despite often not complying with the “rule of five” used in medicinal chemistry to guide the discovery of oral drugs. Here we compare solvent‐dependent three‐dimensional structures of three cyclic hexapeptides containing d ‐amino acids, prolines, and intramolecular hydrogen bonds. Conformational rigidity rather than flexibility resulted in higher membrane permeability, metabolic stability and oral bioavailability, consistent with less polar surface exposure to solvent and a reduced entropy penalty for transition between polar and nonpolar environments.