Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains.
Bioorg Med Chem
; 19(14): 4346-54, 2011 Jul 15.
Article
in En
| MEDLINE
| ID: mdl-21680189
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 ß(B)/ß(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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Intracellular Signaling Peptides and Proteins
/
PDZ Domains
/
Serotonin 5-HT2 Receptor Agonists
/
Membrane Proteins
Type of study:
Prognostic_studies
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2011
Document type:
Article
Affiliation country:
France