Flexibility versus rigidity for orally bioavailable cyclic hexapeptides

Nielsen, Daniel S., Lohman, Rink-Jan, Hoang, Huy Ngoc, Hill, Timothy A., Jones, Alun, Lucke, Andrew J. and Fairlie, David P. (2015) Flexibility versus rigidity for orally bioavailable cyclic hexapeptides. Chembiochem, 16 16: 2289-2293. doi:10.1002/cbic.201500441

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Author Nielsen, Daniel S.
Lohman, Rink-Jan
Hoang, Huy Ngoc
Hill, Timothy A.
Jones, Alun
Lucke, Andrew J.
Fairlie, David P.
Title Flexibility versus rigidity for orally bioavailable cyclic hexapeptides
Journal name Chembiochem   Check publisher's open access policy
ISSN 1439-7633
Publication date 2015-11-02
Year available 2015
Sub-type Article (original research)
DOI 10.1002/cbic.201500441
Open Access Status Not yet assessed
Volume 16
Issue 16
Start page 2289
End page 2293
Total pages 5
Place of publication Weinheim, Germany
Publisher Wiley - V C H Verlag GmbH & Co
Language eng
Subject 1303 Biochemistry
1313 Molecular Medicine
1312 Molecular Biology
1605 Organic Chemistry
Abstract 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.
Keyword Biochemistry & Molecular Biology
Chemistry, Medicinal
Biochemistry & Molecular Biology
Pharmacology & Pharmacy
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID FF0668733
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 19 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 19 times in Scopus Article | Citations
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Created: Wed, 28 Oct 2015, 00:17:58 EST by Susan Allen on behalf of Office of the Vice-Chancellor