title: Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods.
abstract: 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.
authors.affiliation: University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV Groningen (The Netherlands) http://www.drugdesign.nl.
authors.forename: Edwin
authors.initials: E
authors.lastname: Kroon
authors.affiliation: Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt (Germany).
authors.forename: Jörg O
authors.initials: JO
authors.lastname: Schulze
authors.affiliation: Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt (Germany).
authors.forename: Evelyn
authors.initials: E
authors.lastname: Süß
authors.affiliation: University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261 (USA).
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Camacho
authors.affiliation: Universitätsklinikum Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt (Germany).
authors.forename: Ricardo M
authors.initials: RM
authors.lastname: Biondi
authors.affiliation: University of Groningen, Department of Drug Design, A. Deusinglaan 1, 9713 AV Groningen (The Netherlands) http://www.drugdesign.nl. a.s.s.domling@rug.nl.
authors.forename: Alexander
authors.initials: A
authors.lastname: Dömling
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012984:Software
chemical_list: C000631429:PDK1 protein, human; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases
keywords: inhibitors; kinases; pharmacophores; protein-protein interaction; virtual screening