Fragment-Based Discovery and Optimization of Enzyme Inhibitors by Docking of Commercial Chemical Space

Research output: Contribution to journalArticle


Fragment-based lead discovery has emerged as a leading drug development strategy for novel therapeutic targets. Although fragment-based drug discovery benefits immensely from access to atomic-resolution information, structure-based virtual screening has rarely been used to drive fragment discovery and optimization. Here, molecular docking of 0.3 million fragments to a crystal structure of cancer target MTH1 was performed. Twenty-two predicted fragment ligands, for which analogs could be acquired commercially, were experimentally evaluated. Five fragments inhibited MTH1 with IC50 values ranging from 6 to 79 μM. Structure-based optimization guided by predicted binding modes and analogs from commercial chemical libraries yielded nanomolar inhibitors. Subsequently solved crystal structures confirmed binding modes predicted by docking for three scaffolds. Structure-guided exploration of commercial chemical space using molecular docking gives access to fragment libraries that are several orders of magnitude larger than those screened experimentally and can enable efficient optimization of hits to potent leads.


  • Axel Rudling
  • Robert Gustafsson
  • Ingrid Almlöf
  • Evert Homan
  • Martin Scobie
  • Ulrika Warpman Berglund
  • Thomas Helleday
  • Pål Stenmark
  • Jens Carlsson
External organisations
  • Stockholm University
Research areas and keywords


  • Computer Simulation, Crystallography, X-Ray, DNA Repair Enzymes/chemistry, Drug Discovery/methods, Enzyme Inhibitors/chemistry, Humans, Ligands, Models, Molecular, Molecular Docking Simulation, Phosphoric Monoester Hydrolases/chemistry, Protein Binding, Small Molecule Libraries, Structure-Activity Relationship
Original languageEnglish
Pages (from-to)8160-8169
JournalJournal of Medicinal Chemistry
Issue number19
Publication statusPublished - 2017 Oct 12
Publication categoryResearch
Externally publishedYes