Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Computer Simulation
Drug Discovery
/ methods
Enzyme Inhibitors
/ chemistry
High-Throughput Screening Assays
Humans
Inhibitory Concentration 50
Molecular Dynamics Simulation
Monoacylglycerol Lipases
/ antagonists & inhibitors
Piperazines
/ chemistry
Structure-Activity Relationship
Substrate Specificity
MAGL inhibitors
drug design
molecular modelling
virtual screening
Journal
Journal of enzyme inhibition and medicinal chemistry
ISSN: 1475-6374
Titre abrégé: J Enzyme Inhib Med Chem
Pays: England
ID NLM: 101150203
Informations de publication
Date de publication:
Dec 2019
Dec 2019
Historique:
entrez:
31
1
2019
pubmed:
31
1
2019
medline:
7
3
2019
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 30696302
doi: 10.1080/14756366.2019.1571271
pmc: PMC6352951
doi:
Substances chimiques
Enzyme Inhibitors
0
Piperazines
0
Monoacylglycerol Lipases
EC 3.1.1.23
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
589-596Références
Proteins. 2003 Sep 1;52(4):609-23
pubmed: 12910460
J Chem Inf Model. 2007 Mar-Apr;47(2):279-94
pubmed: 17381166
Chem Rev. 2008 May;108(5):1687-707
pubmed: 18429637
Chembiochem. 2008 Nov 3;9(16):2704-10
pubmed: 18855964
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Cell. 2010 Jan 8;140(1):49-61
pubmed: 20079333
Nat Neurosci. 2010 Sep;13(9):1113-9
pubmed: 20729846
Protein Sci. 2011 Apr;20(4):670-83
pubmed: 21308848
J Mol Graph Model. 2011 Apr;29(6):888-93
pubmed: 21310640
J Chem Inf Model. 2011 Mar 28;51(3):578-96
pubmed: 21323318
J Chem Inf Model. 2013 Oct 28;53(10):2538-47
pubmed: 24001328
Bioorg Chem. 2014 Feb;52:16-23
pubmed: 24291035
Bioorg Med Chem. 2014 Jul 1;22(13):3285-91
pubmed: 24853323
J Chem Inf Model. 2014 Oct 27;54(10):2980-6
pubmed: 25211541
J Enzyme Inhib Med Chem. 2015;30(4):662-70
pubmed: 25265323
J Enzyme Inhib Med Chem. 2016;31(1):137-46
pubmed: 25669350
J Chem Inf Model. 2015 Mar 23;55(3):667-75
pubmed: 25746133
J Comput Chem. 2015 Jun 5;36(15):1132-56
pubmed: 25914306
Chem Phys Lipids. 2016 May;197:13-24
pubmed: 26216043
Eur J Med Chem. 2016 May 4;113:11-27
pubmed: 26922225
J Enzyme Inhib Med Chem. 2016;31(sup2):167-173
pubmed: 27311630
J Nat Prod. 2016 Aug 26;79(8):2104-12
pubmed: 27509358
Protein Pept Lett. 2016;23(12):1045-1051
pubmed: 27748182
J Med Chem. 2016 Nov 23;59(22):10299-10314
pubmed: 27809504
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1240-1252
pubmed: 28936880
Expert Opin Ther Pat. 2017 Dec;27(12):1341-1351
pubmed: 29053063
J Enzyme Inhib Med Chem. 2018 Dec;33(1):956-961
pubmed: 29747534
Int J Mol Sci. 2018 Jun 23;19(7):null
pubmed: 29937490
Eur J Med Chem. 2018 Jul 15;155:754-763
pubmed: 29940465
Eur J Med Chem. 2018 Sep 5;157:817-836
pubmed: 30144699
Amino Acids. 2018 Nov;50(11):1595-1605
pubmed: 30145711
Fitoterapia. 2018 Oct;130:251-258
pubmed: 30240845