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

Bouzidi, Naoual; Deokar, Hemantkumar; Vogrig, Alexandre; Boucherle, Benjamin; Ripoche, Isabelle; Abrunhosa-Thomas, Isabelle; Dorr, Liam; Wattiez, Arnaud; Lian, Lu‐Yun; Marin, Philippe; Courteix, Christine; Ducki, Sylvie

doi:10.1016/j.bmcl.2013.02.100

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…Recently, the use of quinoline ligands has shown to specifically inhibit 5-HT 2A receptor/ PSD-95 interactions and to suppress neuropathic pain in rats [40]. These results, together with the present findings, point out the relevance of strategies blocking protein/protein interactions to manage chronic and sub-chronic pain, with presumably less pronounced side effects than classical approaches based on receptor agonists or antagonists.…”

Section: Discussionsupporting

confidence: 77%

Disruption of 5-HT2A Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats

et al. 2013

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Despite common pathophysiological mechanisms, inflammatory and neuropathic pain do not respond equally to the analgesic effect of antidepressants, except for selective serotonin reuptake inhibitors (SSRIs), which show a limited efficacy in both conditions. We previously demonstrated that an interfering peptide (TAT-2ASCV) disrupting the interaction between 5-HT2A receptors and its associated PDZ proteins (e.g. PSD-95) reveals a 5-HT2A receptor-mediated anti-hyperalgesic effect and enhances the efficacy of fluoxetine (a SSRI) in diabetic neuropathic pain conditions in rats. Here, we have examined whether the same strategy would be useful to treat inflammatory pain. Sub-chronic inflammatory pain was induced by injecting λ-carrageenan (100 µl, 2%) into the left hind paw of the rat. Mechanical hyperalgesia was assessed after acute treatment with TAT-2ASCV or/and fluoxetine (SSRI) 2.5 h after λ-carrageenan injection. Possible changes in the level of 5-HT2A receptors and its associated PDZ protein PSD-95 upon inflammation induction were quantified by Western blotting in dorsal horn spinal cord. Administration of TAT-2ASCV peptide (100 ng/rat, intrathecally) but not fluoxetine (10 mg/kg, intraperitoneally) relieves mechanical hyperalgesia (paw pressure test) in inflamed rats. This anti-hyperalgesic effect involves spinal 5-HT2A receptors and GABAergic interneurons as it is abolished by a 5-HT2A antagonist (M100907, 150 ng/rat, intrathecally) and a GABAA antagonist, (bicuculline, 3 µg/rat, intrathecally). We also found a decreased expression of 5-HT2A receptors in the dorsal spinal cord of inflamed animals which could not be rescued by TAT-2ASCV injection, while the amount of PSD-95 was not affected by inflammatory pain. Finally, the coadministration of fluoxetine does not further enhance the anti-hyperalgesic effect of TAT-2ASCV peptide. This study reveals a role of the interactions between 5-HT2A receptors and PDZ proteins in the pathophysiological pathways of inflammatory pain and opens new perspectives in its control thanks to molecules disrupting 5-HT2A receptor/PDZ protein interactions.

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Section: Discussionsupporting

confidence: 77%

Disruption of 5-HT2A Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats

et al. 2013

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“…Besides, isolation of biologically active substances from the plant or animal raw material, their subsequent purification and standardization is, as a rule, difficult and time-consuming. That is why it is quite natural that the search of new analgesics of the quinoline Internet resources reveals a lot of publications concerning the given topics [17][18][19][20][21][22][23]. Thus, promising substances are created based on various derivatives both quinoline (3) itself and its hydrogenized analogs (4).…”

Section: Introductionmentioning

confidence: 99%

4-Hydroxyquinolin-2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-Killers

Украинец¹,

Gorokhova²,

Jaradat³

et al. 2014

Pain and Treatment

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Until recently 4-hydroxyquinolin-2-ones have not even mentioned as analgesics in scientific literature. Only some years ago the situation turned over when based on preliminary virtual screening we obtained hydrochlorides of [(alkylamino)alkyl]amides of 1-allyl-4-hydroxy-6,7dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid as potential opioid receptor antagonists [24]. Further pharmacological research has confirmed the presence of "calculated" Pain and Treatment 22 Pain and Treatment 24 Pain and Treatment 28

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“…Finally, in vivo studies confirmed its ability to reduce the growth rate of prostate cancer cell lines. A similar strategy was used in another study to target the PSD95-PDZ domain [43]. The binding of the best identified fragment (quinoline-2,7-dicarboxylic acid) was confirmed using NMR experiments.…”

Section: Pdz Domains As Potential Drug Targetsmentioning

confidence: 99%

Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

Hoffer

Roché

Morelli

2021

Methods in Molecular Biology

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PDZ domains, which belong to protein-protein interaction networks, are critical for regulating important biological processes such as scaffolding, trafficking and signaling cascades. Interfering with PDZ-mediated interactions could affect these numerous biological processes. Thus, PDZ domains have emerged as promising targets to decipher biological phenomena and potentially treat cancer and neurological diseases. In this minireview, we focus on the discovery and design of small molecule inhibitors to modulate PDZ domains. These compounds interfere with endogenous protein partners from the PDZ domain by binding at the proteinprotein interface. While peptides or peptidomimetic ligands were described to modulate PDZ domains, the focus of this review is on small organic compounds.

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

Cited by 10 publications

References 15 publications

Disruption of 5-HT2A Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats

Disruption of 5-HT2A Receptor-PDZ Protein Interactions Alleviates Mechanical Hypersensitivity in Carrageenan-Induced Inflammation in Rats

4-Hydroxyquinolin-2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-Killers

Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

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