Open AccessStructure-based design, synthesis and crystallization of 2-arylquinazolines as lipid pocket ligands of p38α MAPK
Author(s) -
Mike Bührmann,
Bianca Wiedemann,
Matthias Müller,
Julia Hardick,
Mary Ecke,
Daniel Rauh
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0184627
Subject(s) - kinase , protein kinase a , chemical biology , small molecule , function (biology) , p38 mitogen activated protein kinases , microbiology and biotechnology , biochemistry , mitogen activated protein kinase , binding site , plasma protein binding , enzyme , chemistry , protein function , protein structure , biophysics , computational biology , biology , gene
In protein kinase research, identifying and addressing small molecule binding sites other than the highly conserved ATP-pocket are of intense interest because this line of investigation extends our understanding of kinase function beyond the catalytic phosphotransfer. Such alternative binding sites may be involved in altering the activation state through subtle conformational changes, control cellular enzyme localization, or in mediating and disrupting protein-protein interactions. Small organic molecules that target these less conserved regions might serve as tools for chemical biology research and to probe alternative strategies in targeting protein kinases in disease settings. Here, we present the structure-based design and synthesis of a focused library of 2-arylquinazoline derivatives to target the lipophilic C-terminal binding pocket in p38 α MAPK, for which a clear biological function has yet to be identified. The interactions of the ligands with p38 α MAPK was analyzed by SPR measurements and validated by protein X-ray crystallography.