A Binding Site on IL-17A for Inhibitory Macrocycles Revealed by Hydrogen/Deuterium Exchange Mass Spectrometry

Computational assessment of the IL-17A structure identified two distinct binding pockets, the β-hairpin pocket and the α-helix pocket. The β-hairpin pocket was hypothesized to be the site of binding for peptide macrocycles. Support for this hypothesis was obtained using HDX-MS which revealed protect...

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Veröffentlicht in:	Journal of medicinal chemistry 2016-03, Vol.59 (5), p.2255-2260
Hauptverfasser:	Espada, Alfonso, Broughton, Howard, Jones, Spencer, Chalmers, Michael J, Dodge, Jeffrey A
Format:	Artikel
Sprache:	eng
Schlagworte:	Binding Sites - drug effects Deuterium Exchange Measurement Dose-Response Relationship, Drug Humans Interleukin-17 - antagonists & inhibitors Interleukin-17 - metabolism Macrocyclic Compounds - chemical synthesis Macrocyclic Compounds - chemistry Macrocyclic Compounds - pharmacology Mass Spectrometry Models, Molecular Molecular Conformation Peptides, Cyclic - chemical synthesis Peptides, Cyclic - chemistry Peptides, Cyclic - pharmacology Structure-Activity Relationship
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Beschreibung
Zusammenfassung:	Computational assessment of the IL-17A structure identified two distinct binding pockets, the β-hairpin pocket and the α-helix pocket. The β-hairpin pocket was hypothesized to be the site of binding for peptide macrocycles. Support for this hypothesis was obtained using HDX-MS which revealed protection to exchange only within the β-hairpin pocket. This data represents the first direct structural evidence of a small molecule binding site on IL-17A that functions to disrupt the interaction with its receptor.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/acs.jmedchem.5b01693