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A Multifaceted Secondary Structure Mimic Based On Piperidine‐piperidinones
Author(s) -
Xin Dongyue,
Perez Lisa M.,
Ioerger Thomas R.,
Burgess Kevin
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201400927
Subject(s) - protein secondary structure , chemistry , ideal (ethics) , chemotype , solid state , crystallography , crystal structure , interface (matter) , protein structure , piperidine , computational chemistry , stereochemistry , molecule , organic chemistry , chromatography , biochemistry , epistemology , essential oil , gibbs isotherm , philosophy
Minimalist secondary structure mimics are typically made to resemble one interface in a protein–protein interaction (PPI), and thus perturb it. We recently proposed suitable chemotypes can be matched with interface regions directly, without regard for secondary structures. Here we describe a modular synthesis of a new chemotype 1 , simulation of its solution‐state conformational ensemble, and correlation of that with ideal secondary structures and real interface regions in PPIs. Scaffold 1 presents amino acid side‐chains that are quite separated from each other, in orientations that closely resemble ideal sheet or helical structures, similar non‐ideal structures at PPI interfaces, and regions of other PPI interfaces where the mimic conformation does not resemble any secondary structure. 68 different PPIs where conformations of 1 matched well were identified. A new method is also presented to determine the relevance of a minimalist mimic crystal structure to its solution conformations. Thus dld ‐ 1 faf crystallized in a conformation that is estimated to be 0.91 kcal mol −1 above the minimum energy solution state.