De Novo Fragment Design for Drug Discovery and Chemical Biology

Angew Chem Int Ed Engl. 2015 Dec 7;54(50):15079-83. doi: 10.1002/anie.201508055. Epub 2015 Oct 21.

Abstract

Automated molecular de novo design led to the discovery of an innovative inhibitor of death-associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment-like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery.

Keywords: chemical biology; computational chemistry; kinases; molecular design; target prediction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Death-Associated Protein Kinases / antagonists & inhibitors*
  • Death-Associated Protein Kinases / metabolism
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • DAPK3 protein, human
  • Death-Associated Protein Kinases