Structural and conformational determinants of macrocycle cell permeability.

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 MW, Duvall JR, Kihlberg J

Nat. Chem. Biol. 12 (12) 1065-1074 [2016-12-00; online 2016-10-17]

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.

Affiliated researcher

PubMed 27748751

DOI 10.1038/nchembio.2203

Crossref 10.1038/nchembio.2203