Structural and conformational determinants of macrocycle cell permeability
2016 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, 1065-+ p.Article in journal (Refereed) Published
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 nonpeptidic, 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.
Place, publisher, year, edition, pages
2016. Vol. 12, no 12, 1065-+ p.
IdentifiersURN: urn:nbn:se:uu:diva-311178DOI: 10.1038/NCHEMBIO.2203ISI: 000388582900016PubMedID: 27748751OAI: oai:DiVA.org:uu-311178DiVA: diva2:1059422
FunderAstraZenecaCarl Tryggers foundation Swedish Research Council, 2822