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Structural and conformational determinants of macrocycle cell permeability
AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2016 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, 1065-+ p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-311178DOI: 10.1038/NCHEMBIO.2203ISI: 000388582900016PubMedID: 27748751OAI: oai:DiVA.org:uu-311178DiVA: diva2:1059422
Funder
AstraZenecaCarl Tryggers foundation Swedish Research Council, 2822
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2016-12-22Bibliographically approved

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Matsson, PärArtursson, PerDoak, Bradley C.Kihlberg, Jan
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