Biomaterial Database

Structural and conformational determinants of macrocycle cell permeability. 2016

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

Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca R&D Gothenburg, Mölndal, Sweden.

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.

UI	MeSH Term	Description	Entries
D010539	Permeability	Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions.	Permeabilities
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013237	Stereoisomerism	The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)	Molecular Stereochemistry,Stereoisomers,Stereochemistry, Molecular,Stereoisomer
D013329	Structure-Activity Relationship	The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.	Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D015394	Molecular Structure	The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.	Structure, Molecular,Molecular Structures,Structures, Molecular
D047028	Macrocyclic Compounds	Cyclic compounds with a ring size of approximately 1-4 dozen atoms.	Macrocycle Compounds,Spherands,Torands,Compounds, Macrocycle,Compounds, Macrocyclic
D018938	Caco-2 Cells	Human colonic ADENOCARCINOMA cells that are able to express differentiation features characteristic of mature intestinal cells, such as ENTEROCYTES. These cells are valuable in vitro tools for studies related to intestinal cell function and differentiation.	Caco 2 Cells,Caco-2 Cell,Cell, Caco-2,Cells, Caco-2