Flexibility versus Rigidity for Orally Bioavailable Cyclic Hexapeptides

Chembiochem : a European Journal of Chemical Biology
Daniel S NielsenDavid P Fairlie

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.

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Sep 16, 2014·Angewandte Chemie·Daniel S NielsenDavid P Fairlie

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Citations

Apr 1, 2016·Journal of Chemical Theory and Computation·Sean M McHughYu-Shan Lin
Aug 27, 2016·ACS Medicinal Chemistry Letters·Joshua SchwochertR Scott Lokey
Apr 20, 2016·Biotechnology and Bioengineering·Soohyun KwonDavid J Craik
Oct 11, 2016·Expert Opinion on Drug Discovery·Andrew M White, David J Craik
May 15, 2016·Biopolymers·Conan K Wang, David J Craik
May 26, 2017·Chemical Reviews·Daniel S NielsenDavid P Fairlie
Jan 17, 2017·Physical Chemistry Chemical Physics : PCCP·Sean M McHughYu-Shan Lin
Oct 21, 2017·Chemical Biology & Drug Design·Tyrslai M WilliamsSeetharama D Jois
Sep 7, 2017·Organic & Biomolecular Chemistry·Adrian WhittyMengqi Zhong
Jul 11, 2018·Chemistry : a European Journal·Luis M De Leon RodriguezMargaret A Brimble
Oct 22, 2019·Chemical Communications : Chem Comm·Rink-Jan LohmanDavid P Fairlie
Jun 21, 2017·Chemistry : a European Journal·Akira MizunoSatoshi Shuto
Apr 14, 2019·Pharmaceuticals·Rachel Hevey
Sep 3, 2020·Chemistry : a European Journal·Laura K BucktonShelli R McAlpine
Dec 18, 2020·International Journal of Toxicology·Doris ZaneJessica Hawes
Jun 2, 2020·Advanced Drug Delivery Reviews·D J BraydenR J Mrsny
Aug 14, 2020·Chemical Reviews·Rasha JwadLuke Hunter
Oct 6, 2020·Journal of Medicinal Chemistry·Dan SindhikaraAndreas Evers
Jun 20, 2020·Journal of Chemical Information and Modeling·Anna S KamenikKlaus R Liedl
Feb 16, 2019·Journal of the American Chemical Society·Alexander A VinogradovHiroaki Suga
Dec 7, 2018·Chemical Reviews·Teresa L MakoMindy Levine
Aug 15, 2019·Chemical Reviews·Solomon D AppavooAndrei K Yudin

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