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

Journal of Enzyme Inhibition and Medicinal Chemistry

Margherita Lapillo¹  Filippo Minutolo¹  Giulio Poli¹  Vibhu Jha¹  Marco Macchia¹  Tiziano Tuccinardi¹  Nayla Mouawad²  Carlotta Granchi³  Isabella Caligiuri⁴  Flavio Rizzolio⁵ 

[1] Department of Pharmacy, University of Pisa, Pisa, Italy;Department of Pharmacy, University of Pisa, Pisa, Italy;Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano, Italy;Department of Pharmacy, University of Pisa, Pisa, Italy;Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, US;Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano, Italy;Pathology Unit, Department of Molecular Biology and Translational Research, National Cancer Institute and Center for Molecular Biomedicine, Aviano, Italy;Department of Molecular Science and Nanosystems, Ca' Foscari Università di Venezia, Venezia, Italy;

关键词: MAGL inhibitors;    virtual screening;    molecular modelling;    drug design;   

DOI  :  10.1080/14756366.2019.1571271

来源: publisher

【 摘 要 】

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 (IC50 = 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.

【 授权许可】

CC BY