Identification of PDZ ligands by docking-based virtual screening for the development of novel analgesic agents

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 9; pp. 2624 - 2627
• Main Authors: Bouzidi, Naoual, Deokar, Hemantkumar, Vogrig, Alexandre, Boucherle, Benjamin, Ripoche, Isabelle, Abrunhosa-Thomas, Isabelle, Dorr, Liam, Wattiez, Anne-Sophie, Lian, Lu-Yun, Marin, Philippe, Courteix, Christine, Ducki, Sylvie
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.05.2013; Elsevier
• Subjects: Analgesic activity; analgesic effect; analgesics; Analgesics - chemical synthesis; Analgesics - chemistry; Analgesics - therapeutic use; Animals; Binding Sites; Biochemistry; Biochemistry, Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Docking-based virtual screening; Drug Design; filters; glutamic acid; Life Sciences; Life Sciences & Biomedicine; Ligands; Molecular Docking Simulation; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Neuralgia - drug therapy; nuclear magnetic resonance spectroscopy; Pain; PDZ Domains; PDZ proteins; Pharmacology & Pharmacy; Physical Sciences; quinoline; Quinolines - chemistry; Rats; Receptor, Serotonin, 5-HT2A - chemistry; Receptor, Serotonin, 5-HT2A - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - metabolism; SAP90-PSD95 Associated Proteins; Science & Technology; screening; serotonin; PDZ proteins; Docking-based virtual screening; Pain; Analgesic activity; DOMAIN; 5-HT2A
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.02.100

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.