Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods.
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.
['Kroon|Edwin|E|', 'Schulze|Jörg O|JO|', 'Süß|Evelyn|E|', 'Camacho|Carlos J|CJ|', 'Biondi|Ricardo M|RM|', 'Dömling|Alexander|A|']
D000494:Allosteric Regulation D055808:Drug Discovery D006801:Humans D008958:Models, Molecular D015394:Molecular Structure D047428:Protein Kinase Inhibitors D017346:Protein Serine-Threonine Kinases D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase D012984:Software
kinases inhibitors pharmacophores protein-protein interaction virtual screening