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Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods
Author(s) -
Kroon Edwin,
Schulze Jörg O.,
Süß Evelyn,
Camacho Carlos J.,
Biondi Ricardo M.,
Dömling Alexander
Publication year - 2015
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.201506310
Subject(s) - allosteric regulation , drug discovery , kinase , chemistry , computational biology , rational design , allosteric modulator , drug design , computer science , biochemistry , nanotechnology , biology , enzyme , materials science
The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth‐factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells. ANCHOR.QUERY software was used to discover a potent allosteric PDK1 kinase modulator. Using a recently published PDK1 compound as a template, several new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERY approach. Our results are significant because the outlined approach allows rapid and efficient scaffold hopping from known molecules into new easily accessible and biologically active ones. Based on increasing interest in allosteric‐site drug discovery, we foresee many potential applications for this approach.