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Drugs by Numbers: Reaction-Driven De Novo Design of Potent and Selective Anticancer Leads


  • We thank Dr. M. Bieler for computing QED values and Sarah Haller for technical support. Dr. T. Geppert performed the computational docking experiment. Dr. M. Rupp contributed the ISOAK similarity function to DOGS. This research was financially supported by the Deutsche Krebshilfe (grant no. 108651), the Wilhelm-Sander-Stiftung (grant no. 2009.024.1), the Messer-Stiftung (to B.S.), the Swiss National Science Foundation (grant no. 205321-134783), and the Deutsche Forschungsgemeinschaft (grant no. FOR1406TP4) (to G.S.). B.S. is grateful to Dr. D. Wallwiener for providing working facilities. G.S. is grateful to the Chemical Computing Group, Inc. (Montreal, Canada) for a research license of MOE.


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A potent and selective inhibitor of the anticancer target Polo-like kinase 1 was found by computer-based molecular design. This type II kinase inhibitor was synthesized as suggested by the design software DOGS and exhibited significant antiproliferative effects against HeLa cells without affecting nontransformed cells. The study provides a proof-of-concept for reaction-based de novo design as a leading tool for drug discovery.