Mapping the binding sites of challenging drug targets

Curr Opin Struct Biol. 2022 Aug;75:102396. doi: 10.1016/ Epub 2022 May 27.


An increasing number of medically important proteins are challenging drug targets because their binding sites are too shallow or too polar, are cryptic and thus not detectable without a bound ligand or located in a protein-protein interface. While such proteins may not bind druglike small molecules with sufficiently high affinity, they are frequently druggable using novel therapeutic modalities. The need for such modalities can be determined by experimental or computational fragment based methods. Computational mapping by mixed solvent molecular dynamics simulations or the FTMap server can be used to determine binding hot spots. The strength and location of the hot spots provide very useful information for selecting potentially successful approaches to drug discovery.

Keywords: Allosteric sites; Beyond rule of five compounds; Cryptic sites; Inhibitors of protein–protein interactions; Mixed solvent molecular dynamics.

Publication types

  • Review
  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Drug Discovery
  • Ligands
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Proteins* / chemistry


  • Ligands
  • Proteins