Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

J Med Chem. 2018 Aug 9;61(15):6830-6845. doi: 10.1021/acs.jmedchem.8b00718. Epub 2018 Jul 24.


To investigate large library docking's ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D2 and serotonin 5-HT2A receptors were targeted, seeking selectivity against the histamine H1 receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D2/5-HT2A ligand with 21-fold selectivity versus the H1 receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field.

MeSH terms

  • Drug Evaluation, Preclinical
  • Ligands
  • Molecular Docking Simulation*
  • Protein Conformation
  • Receptor, Serotonin, 5-HT2A / chemistry
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / metabolism*
  • Substrate Specificity


  • Ligands
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2