Benzisothiazolinone Derivatives as Potent Allosteric Monoacylglycerol Lipase Inhibitors That Functionally Mimic Sulfenylation of Regulatory Cysteines
| Autor: | Kasper D. Rand, Marco Mor, Caterina Carmi, Michele Bassi, Ingvar R. Möller, Emmanuel Y. Dotsey, Daniele Piomelli, Alessio Lodola, Faizy Ahmed, Don Wei, Nephi Stella, Federica Vacondio, Jennifer Daglian, Simar Singh, Riccardo Castelli, Silvia Rivara, Mattia Anselmi, Kwang-Mook Jung, Stefano Vezzosi, Laura Scalvini, Francesca Ferlenghi |
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| Rok vydání: | 2019 |
| Předmět: |
Stereochemistry
Allosteric regulation Plasma protein binding 01 natural sciences Mice Structure-Activity Relationship 03 medical and health sciences Allosteric Regulation Drug Discovery Animals Humans Structure–activity relationship Cysteine Enzyme Inhibitors Binding site 030304 developmental biology chemistry.chemical_classification 0303 health sciences Binding Sites Molecular Structure Mutagenesis Endocannabinoid system Monoacylglycerol Lipases Rats 0104 chemical sciences Molecular Docking Simulation Monoacylglycerol lipase Thiazoles 010404 medicinal & biomolecular chemistry Enzyme chemistry Mutation Mutagenesis Site-Directed Molecular Medicine Oxidation-Reduction HeLa Cells Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 63:1261-1280 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | We describe a set of benzisothiazolinone (BTZ) derivatives that are potent inhibitors of monoacylglycerol lipase (MGL), the primary degrading enzyme for the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Structure-activity relationship studies evaluated various substitutions on the nitrogen atom and the benzene ring of the BTZ nucleus. Optimized derivatives with nanomolar potency allowed us to investigate the mechanism of MGL inhibition. Site-directed mutagenesis and mass spectrometry experiments showed that BTZs interact in a covalent reversible manner with regulatory cysteines, Cys201 and Cys208, causing a reversible sulfenylation known to modulate MGL activity. Metadynamics simulations revealed that BTZ adducts favor a closed conformation of MGL that occludes substrate recruitment. The BTZ derivative 13 protected neuronal cells from oxidative stimuli and increased 2-AG levels in the mouse brain. The results identify Cys201 and Cys208 as key regulators of MGL function and point to the BTZ scaffold as a useful starting point for the discovery of allosteric MGL inhibitors. |
| Databáze: | OpenAIRE |
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