title: Reaction-driven de novo design, synthesis and testing of potential type II kinase inhibitors.
abstract: BACKGROUND
  De novo design of drug-like compounds with a desired pharmacological activity profile has become feasible through innovative computer algorithms. Fragment-based design and simulated chemical reactions allow for the rapid generation of candidate compounds as blueprints for organic synthesis.
  
  
  METHODS
  We used a combination of complementary virtual-screening tools for the analysis of de novo designed compounds that were generated with the aim to inhibit inactive polo-like kinase 1 (Plk1), a target for the development of cancer therapeutics. A homology model of the inactive state of Plk1 was constructed and the nucleotide binding pocket conformations in the DFG-in and DFG-out state were compared. The de novo-designed compounds were analyzed using pharmacophore matching, structure-activity landscape analysis, and automated ligand docking. One compound was synthesized and tested in vitro.
  
  
  RESULTS
  The majority of the designed compounds possess a generic architecture present in known kinase inhibitors. Predictions favor kinases as targets of these compounds but also suggest potential off-target effects. Several bioisosteric replacements were suggested, and de novo designed compounds were assessed by automated docking for potential binding preference toward the inactive (type II inhibitors) over the active conformation (type I inhibitors) of the kinase ATP binding site. One selected compound was successfully synthesized as suggested by the software. The de novo-designed compound exhibited inhibitory activity against inactive Plk1 in vitro, but did not show significant inhibition of active Plk1 and 38 other kinases tested.
  
  
  CONCLUSIONS
  Computer-based de novo design of screening candidates in combination with ligand- and receptor-based virtual screening generates motivated suggestions for focused library design in hit and lead discovery. Attractive, synthetically accessible compounds can be obtained together with predicted on- and off-target profiles and desired activities.
authors: Swiss Federal Institute of Technology, Department of Chemistry & Applied Biosciences, 8093 Zürich, Switzerland. gisbert.schneider@pharma.ethz.ch
authors: Gisbert
authors: G
authors: Schneider
authors: Tim
authors: T
authors: Geppert
authors: Markus
authors: M
authors: Hartenfeller
authors: Felix
authors: F
authors: Reisen
authors: Alexander
authors: A
authors: Klenner
authors: Michael
authors: M
authors: Reutlinger
authors: Volker
authors: V
authors: Hähnke
authors: Jan A
authors: JA
authors: Hiss
authors: Heiko
authors: H
authors: Zettl
authors: Sarah
authors: S
authors: Keppner
authors: Birgit
authors: B
authors: Spänkuch
authors: Petra
authors: P
authors: Schneider
mesh_terms: D001185:Artificial Intelligence; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D008024:Ligands; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012984:Software; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D008024:Ligands; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1