title: Identification of PDZ ligands by docking-based virtual screening for the development of novel analgesic agents.
abstract: Disrupting the interaction between the PDZ protein, PSD-95, and its target ligands (such as the glutamate NMDA receptor or the serotonin 5-HT2A receptor) was found to reduce hyperalgesia in various models of neuropathic pain. Here, we set out to identify lead molecules which would interact with PSD-95, and hence, would potentially display analgesic activity. We describe the virtual screening of the Asinex and Cambridge databases which together contain almost one million molecules. Using three successive docking filters and visual inspection, we identified three structural classes of molecules and synthesized a potential lead compound from each class. The binding of the molecules with the PDZ domains of PSD-95 was assessed by (1)H-(15)N HSQC NMR experiments. The analgesic activity of the best ligand, quinoline 2, was evaluated in vivo in a model of neuropathic pain and showed promising results.
authors.affiliation: Clermont Université, UBP, CNRS UMR 6296, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France.
authors.forename: Naoual
authors.initials: N
authors.lastname: Bouzidi
authors.forename: Hemantkumar
authors.initials: H
authors.lastname: Deokar
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vogrig
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boucherle
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ripoche
authors.forename: Isabelle
authors.initials: I
authors.lastname: Abrunhosa-Thomas
authors.forename: Liam
authors.initials: L
authors.lastname: Dorr
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Wattiez
authors.forename: Lu-Yun
authors.initials: LY
authors.lastname: Lian
authors.forename: Philippe
authors.initials: P
authors.lastname: Marin
authors.forename: Christine
authors.initials: C
authors.lastname: Courteix
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducki
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D008024:Ligands; D062105:Molecular Docking Simulation; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy; D054731:PDZ Domains; D011804:Quinolines / Q000737:chemistry; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000074407:SAP90-PSD95 Associated Proteins
chemical_list: D000700:Analgesics; D008024:Ligands; D009419:Nerve Tissue Proteins; D011804:Quinolines; D044402:Receptor, Serotonin, 5-HT2A; D016194:Receptors, N-Methyl-D-Aspartate; D000074407:SAP90-PSD95 Associated Proteins; C037219:quinoline