Identification of PDZ ligands by docking-based virtual screening for the development of novel analgesic agents |
| |
Authors: | Naoual Bouzidi Hemantkumar Deokar Alexandre Vogrig Benjamin Boucherle Isabelle Ripoche Isabelle Abrunhosa-Thomas Liam Dorr Anne-Sophie Wattiez Lu-Yun Lian Philippe Marin Christine Courteix Sylvie Ducki |
| |
Affiliation: | 1. Clermont Université, UBP, CNRS UMR 6296, Institut de Chimie de Clermont-Ferrand, BP 10448, F-63000 Clermont-Ferrand, France;2. Clermont Université, ENSCCF, CNRS UMR 6296, Institut de Chimie de Clermont-Ferrand, BP 10187, F-63174 Aubière, France;3. NMR Centre for Structural Biology, University of Liverpool, UK-L69 3BX Liverpool, UK;4. Clermont Université, Université d’Auvergne, Institut NeuroDol, BP 10448, F-63000 Clermont-Ferrand, INSERM, UMR 1107, F-63001 Clermont-Ferrand, France;5. IGF, CNRS UMR 5203, INSERM U661, Universités Montpellier 1&2, F-34094 Montpellier, France |
| |
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 1H–15N 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. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|