Identification and characterization of a new reversible MAGL inhibitor.
Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (Ki=8.6μM), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases.
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy. Electronic address: tiziano.tuccinardi@farm.unipi.it.
Tiziano
T
Tuccinardi
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Carlotta
C
Granchi
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, CRO National Cancer Institute and Center for Molecular Biomedicine, IRCCS, Aviano (PN), Italy.
Flavio
F
Rizzolio
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, CRO National Cancer Institute and Center for Molecular Biomedicine, IRCCS, Aviano (PN), Italy.
Isabella
I
Caligiuri
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Vittoria
V
Battistello
Division of Experimental and Clinical Pharmacology, Department of Molecular Biology and Translational Research, CRO National Cancer Institute and Center for Molecular Biomedicine, IRCCS, Aviano (PN), Italy.
Giuseppe
G
Toffoli
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Filippo
F
Minutolo
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Marco
M
Macchia
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Adriano
A
Martinelli
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases
Hydrolase; MAGL; Monoacylglycerol lipase inhibitors; Virtual screening