|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Over, B, Matsson, P, Tyrchan, C, Artursson, P, Doak, BC, Foley, MA, Hilgendorf, C, Johnston, SE, Lee, MD, Lewis, RJ, McCarren, P, Muncipinto, G, Norinder, U, Perry, MWD, Duvall, JR, Kihlberg, J|
|Journal||Nat Chem Biol|
|Date Published||2016 Dec|
|Keywords||Caco-2 Cells, Humans, Macrocyclic Compounds, Molecular Structure, Permeability, Stereoisomerism, Structure-Activity Relationship|
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.
|Alternate Journal||Nat. Chem. Biol.|