Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides. Issue 16 (7th October 2015)

• Record Type: Journal Article
• Authors: Nielsen, Daniel S.; Lohman, Rink‐Jan; Hoang, Huy N.; Hill, Timothy A.; Jones, Alun; Lucke, Andrew J.; Fairlie, David P.
• Is Part Of: Chembiochem. Volume 16:Issue 16(2015)
• Page Start: 2289
• Page End: 2293
• Publication Date: 2015-10-07
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500441
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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 <sc>d</sc>‐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.</p> </abstract>