Structural and conformational determinants of macrocycle cell permeability

• DOI: 10.1038/nchembio.2203
• Publication Date: 2016-10-17T15:48:23Z
• Authors: Björn Over; Pär Matsson; Christian Tyrchan; Per Artursson; Bradley C Doak; Michael A Foley; Constanze Hilgendorf; Stephen E Johnston; Maurice D Lee; Richard J Lewis; Patrick McCarren; Giovanni Muncipinto; Ulf Norinder; Matthew W D Perry; Jeremy R Duvall; Jan Kihlberg
• Keywords: Cell permeability; Rational design

Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 non-peptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.