Structural and conformational determinants of macrocycle cell permeability

Björn Over; Pär Matsson; Christian Tyrchan; Per Artursson; Bradley C Doak; Michael A Foley; Constanze Hilgendorf; Stephen E Johnston; Maurice D Lee 4th; Richard J Lewis; Patrick McCarren; Giovanni Muncipinto; Ulf Norinder; Matthew W D Perry; Jeremy R Duvall; Jan Kihlberg

doi:10.1038/nchembio.2203

Structural and conformational determinants of macrocycle cell permeability

Nat Chem Biol. 2016 Dec;12(12):1065-1074. doi: 10.1038/nchembio.2203. Epub 2016 Oct 17.

Authors

Björn Over¹, Pär Matsson^{2

3}, Christian Tyrchan⁴, Per Artursson^{2

3}, Bradley C Doak⁵, Michael A Foley⁶, Constanze Hilgendorf⁷, Stephen E Johnston⁶, Maurice D Lee 4th⁶, Richard J Lewis⁴, Patrick McCarren⁶, Giovanni Muncipinto⁶, Ulf Norinder⁸, Matthew W D Perry⁴, Jeremy R Duvall⁶, Jan Kihlberg⁵

Affiliations

¹ Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
² Department of Pharmacy, Uppsala University, Uppsala, Sweden.
³ Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), a node at the Chemical Biology Consortium Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
⁴ Respiratory, Inflammation and Autoimmunity Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
⁵ Department of Chemistry, Uppsala University, Uppsala, Sweden.
⁶ Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts, USA.
⁷ Drug Safety and Metabolism, Safety &ADME Translational Sciences, AstraZeneca R&D Gothenburg, Mölndal, Sweden.
⁸ Swedish Toxicology Sciences Research Center, Södertälje, Sweden.

PMID: 27748751
DOI: 10.1038/nchembio.2203

Abstract

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.

MeSH terms

Caco-2 Cells
Humans
Macrocyclic Compounds / chemistry*
Macrocyclic Compounds / pharmacokinetics*
Molecular Structure
Permeability
Stereoisomerism
Structure-Activity Relationship

Substances

Macrocyclic Compounds

Associated data

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