Protocol

Fragment-Based Methods in Drug Discovery

Volume 1289 of the series Methods in Molecular Biology pp 57-73

Date:

Protocol for Fragment Hopping

  • Kevin B. TeuscherAffiliated withDepartment of Chemistry, Center for Cell and Genome Science, University of Utah
  • , Haitao JiAffiliated withDepartment of Chemistry, Center for Cell and Genome Science, University of Utah Email author 

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Abstract

Fragment hopping is a fragment-based approach to designing biologically active small molecules. The key of this approach is the determination of the minimal pharmacophoric elements in the three-dimensional space. Based on the derived minimal pharmacophoric elements, new fragments with different chemotypes can be generated and positioned to the active site of the target protein. Herein, we detail a protocol for performing fragment hopping. This approach can not only explore a wide chemical space to produce new ligands with novel scaffolds but also characterize and utilize the delicate differences in the active sites between isofunctional proteins to produce new ligands with high target selectivity/specificity.

Key words

Fragment-based drug discovery Fragment hopping Scaffold diversity Isofunctional proteins Protein–protein interactions Inhibitors Selectivity Peptidomimetics