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

pii: nchembio.2203
PubChem-Substance: 318122242
PubChem-Substance: 318122253
PubChem-Substance: 318122264
PubChem-Substance: 318122269
PubChem-Substance: 318122270
PubChem-Substance: 318122271
PubChem-Substance: 318122272
PubChem-Substance: 318122273
PubChem-Substance: 318122274
PubChem-Substance: 318122243
PubChem-Substance: 318122244
PubChem-Substance: 318122245
PubChem-Substance: 318122246
PubChem-Substance: 318122247
PubChem-Substance: 318122248
PubChem-Substance: 318122249
PubChem-Substance: 318122250
PubChem-Substance: 318122251
PubChem-Substance: 318122252
PubChem-Substance: 318122254
PubChem-Substance: 318122255
PubChem-Substance: 318122256
PubChem-Substance: 318122257
PubChem-Substance: 318122258
PubChem-Substance: 318122259
PubChem-Substance: 318122260
PubChem-Substance: 318122261
PubChem-Substance: 318122262
PubChem-Substance: 318122263
PubChem-Substance: 318122265
PubChem-Substance: 318122266
PubChem-Substance: 318122267
PubChem-Substance: 318122268


Publications 9.5.0