Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

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  • Additional Information
    • Source:
      Publisher: Taylor & Francis Country of Publication: England NLM ID: 101150203 Publication Model: Print Cited Medium: Internet ISSN: 1475-6374 (Electronic) Linking ISSN: 14756366 NLM ISO Abbreviation: J Enzyme Inhib Med Chem Subsets: MEDLINE
    • Publication Information:
      Original Publication: Basingstoke, UK : Taylor & Francis, c2002-
    • Subject Terms:
    • Abstract:
      Monoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC 50 = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC 50 of 31-72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed.
    • References:
      Proteins. 2003 Sep 1;52(4):609-23. (PMID: 12910460)
      J Chem Inf Model. 2007 Mar-Apr;47(2):279-94. (PMID: 17381166)
      Chem Rev. 2008 May;108(5):1687-707. (PMID: 18429637)
      Chembiochem. 2008 Nov 3;9(16):2704-10. (PMID: 18855964)
      J Comput Chem. 2009 Dec;30(16):2785-91. (PMID: 19399780)
      Cell. 2010 Jan 8;140(1):49-61. (PMID: 20079333)
      Nat Neurosci. 2010 Sep;13(9):1113-9. (PMID: 20729846)
      Protein Sci. 2011 Apr;20(4):670-83. (PMID: 21308848)
      J Mol Graph Model. 2011 Apr;29(6):888-93. (PMID: 21310640)
      J Chem Inf Model. 2011 Mar 28;51(3):578-96. (PMID: 21323318)
      J Chem Inf Model. 2013 Oct 28;53(10):2538-47. (PMID: 24001328)
      Bioorg Chem. 2014 Feb;52:16-23. (PMID: 24291035)
      Bioorg Med Chem. 2014 Jul 1;22(13):3285-91. (PMID: 24853323)
      J Chem Inf Model. 2014 Oct 27;54(10):2980-6. (PMID: 25211541)
      J Enzyme Inhib Med Chem. 2015;30(4):662-70. (PMID: 25265323)
      J Enzyme Inhib Med Chem. 2016;31(1):137-46. (PMID: 25669350)
      J Chem Inf Model. 2015 Mar 23;55(3):667-75. (PMID: 25746133)
      J Comput Chem. 2015 Jun 5;36(15):1132-56. (PMID: 25914306)
      Chem Phys Lipids. 2016 May;197:13-24. (PMID: 26216043)
      Eur J Med Chem. 2016 May 4;113:11-27. (PMID: 26922225)
      J Enzyme Inhib Med Chem. 2016;31(sup2):167-173. (PMID: 27311630)
      J Nat Prod. 2016 Aug 26;79(8):2104-12. (PMID: 27509358)
      Protein Pept Lett. 2016;23(12):1045-1051. (PMID: 27748182)
      J Med Chem. 2016 Nov 23;59(22):10299-10314. (PMID: 27809504)
      J Enzyme Inhib Med Chem. 2017 Dec;32(1):1240-1252. (PMID: 28936880)
      Expert Opin Ther Pat. 2017 Dec;27(12):1341-1351. (PMID: 29053063)
      J Enzyme Inhib Med Chem. 2018 Dec;33(1):956-961. (PMID: 29747534)
      Int J Mol Sci. 2018 Jun 23;19(7):null. (PMID: 29937490)
      Eur J Med Chem. 2018 Jul 15;155:754-763. (PMID: 29940465)
      Eur J Med Chem. 2018 Sep 5;157:817-836. (PMID: 30144699)
      Amino Acids. 2018 Nov;50(11):1595-1605. (PMID: 30145711)
      Fitoterapia. 2018 Oct;130:251-258. (PMID: 30240845)
    • Contributed Indexing:
      Keywords: MAGL inhibitors; drug design; molecular modelling; virtual screening
    • Accession Number:
      0 (Enzyme Inhibitors)
      0 (Piperazines)
      EC 3.1.1.23 (Monoacylglycerol Lipases)
    • Publication Date:
      Date Created: 20190131 Date Completed: 20190306 Latest Revision: 20200225
    • Publication Date:
      20240104
    • Accession Number:
      PMC6352951
    • Accession Number:
      10.1080/14756366.2019.1571271
    • Accession Number:
      30696302