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

Giulio Poli, Margherita Lapillo, Vibhu Jha, Nayla Mouawad, Isabella Caligiuri, Marco Macchia, Filippo Minutolo, Flavio Rizzolio, Tiziano Tuccinardi, Carlotta Granchi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)589-596
Number of pages8
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume34
Issue number1
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • drug design
  • MAGL inhibitors
  • molecular modelling
  • virtual screening

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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