title: Synthesis and evaluation of bidentate ligands designed to interact with PDZ domains.
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.
authors.affiliation: Clermont Université, UBP, EA 987, LCHG, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boucherle
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vogrig
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Deokar
authors.forename: Naoual
authors.initials: N
authors.lastname: Bouzidi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ripoche
authors.forename: Isabelle
authors.initials: I
authors.lastname: Thomas
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducki
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D019295:Computational Biology; D000076122:Disks Large Homolog 4 Protein; D015195:Drug Design; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D054731:PDZ Domains / Q000187:drug effects*; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists