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Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.
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- Author(s): Poli G;Poli G; Lapillo M; Lapillo M; Jha V; Jha V; Mouawad N; Mouawad N; Mouawad N; Caligiuri I; Caligiuri I; Macchia M; Macchia M; Minutolo F; Minutolo F; Rizzolio F; Rizzolio F; Rizzolio F; Tuccinardi T; Tuccinardi T; Granchi C; Granchi C; Granchi C
- Source:
Journal of enzyme inhibition and medicinal chemistry [J Enzyme Inhib Med Chem] 2019 Dec; Vol. 34 (1), pp. 589-596.- Publication Type:
Journal Article- Language:
English - Source:
- 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: Computer Simulation*; Drug Discovery/*methods ; Enzyme Inhibitors/*chemistry ; Enzyme Inhibitors/*pharmacology ; Monoacylglycerol Lipases/*antagonists & inhibitors ; Piperazines/*chemistry ; Piperazines/*pharmacology; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; High-Throughput Screening Assays ; Humans ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Monoacylglycerol Lipases/metabolism ; Structure-Activity Relationship ; Substrate Specificity
- 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 (IC50 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)
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- 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
- Source:
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