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Structural and conformational determinants of macrocycle cell permeability
AstraZeneca R&D Gothenburg, Mölndal, Sweden.
Department of Pharmacy, Uppsala University, Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.ORCID iD: 0000-0002-9094-2581
AstraZeneca R&D Gothenburg, Mölndal, Sweden.
Department of Pharmacy, Uppsala University, Uppsala, Sweden; Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala University, Uppsala, Sweden.
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2016 (English)In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, p. 1065-1074Article 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
New York: Nature Publishing Group, 2016. Vol. 12, no 12, p. 1065-1074
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:oru:diva-83153DOI: 10.1038/NCHEMBIO.2203ISI: 000388582900016PubMedID: 27748751Scopus ID: 2-s2.0-84991737663OAI: oai:DiVA.org:oru-83153DiVA, id: diva2:1440472
Funder
AstraZenecaSwedish Research Council, 2822Carl Tryggers foundation
Note

Delat förstaförfattarskap: Bjorn Over, Pär Matsson

(Shared first authorship: Bjorn Over, Pär Matsson)

Ytterligare forskningsfinansiär: NIGMS-Center of Excellence in Chemical Methodology and Library Development (Broad Institute CMLD), Grant Number: P50 GM069721

Available from: 2016-12-22 Created: 2020-06-15 Last updated: 2024-01-16Bibliographically approved

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Matsson, PärArtursson, PerDoak, Bradley C.Norinder, UlfKihlberg, Jan

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