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Structural and conformational determinants of macrocycle cell permeability.

Björn OverPär MatssonChristian TyrchanPer ArturssonBradley C DoakMichael A FoleyConstanze HilgendorfStephen E JohnstonMaurice D LeeRichard J LewisPatrick McCarrenGiovanni MuncipintoUlf NorinderMatthew W D PerryJeremy R DuvallJan Kihlberg
Published in: Nature chemical biology (2016)
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.
Keyphrases
  • single cell
  • cell therapy
  • endothelial cells
  • single molecule
  • molecular dynamics
  • high resolution
  • machine learning
  • mesenchymal stem cells
  • risk assessment
  • deep learning