Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains

Bioorg Med Chem. 2011 Jul 15;19(14):4346-54. doi: 10.1016/j.bmc.2011.05.036. Epub 2011 May 24.

Abstract

We designed bidentate ligands to target PDZ domains through two binding sites: site S0, delimited by the GLGF loop, and site S1, a zone situated around loop β(B)/β(C). A molecular docking study allowed us to design a generic S0 binder, to which was attached a variable size linker, itself linked to an amino acid aimed to interact with the S1 site of PDZ domains. A series of 15 novel bidentate ligands was prepared in 6-11 steps in good overall yield (24-43%). Some of these ligands showed an inhibitory activity against serotonin 5-HT2A receptor/PSD-95 interaction. This was assessed by pull-down assay using a synthetic decapeptide corresponding to the C-terminal residues of the receptor as a bait.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Computational Biology
  • Disks Large Homolog 4 Protein
  • Drug Design*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Ligands
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / chemistry
  • Models, Molecular
  • Molecular Conformation
  • PDZ Domains / drug effects*
  • Receptor, Serotonin, 5-HT2A / chemistry
  • Receptor, Serotonin, 5-HT2A / metabolism
  • Serotonin 5-HT2 Receptor Agonists / chemical synthesis
  • Serotonin 5-HT2 Receptor Agonists / chemistry
  • Serotonin 5-HT2 Receptor Agonists / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • DLG4 protein, human
  • Disks Large Homolog 4 Protein
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Membrane Proteins
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Agonists