Dotsey EY

References (2)

Title : Benzisothiazolinone derivatives as potent allosteric monoacylglycerol lipase inhibitors that functionally mimic sulfenylation of regulatory cysteines - Castelli_2020_J.Med.Chem_63_1261
Author(s) : Castelli R , Scalvini L , Vacondio F , Lodola A , Anselmi M , Vezzosi S , Carmi C , Bassi M , Ferlenghi F , Rivara S , Moller IR , Rand KD , Daglian J , Wei D , Dotsey EY , Ahmed F , Jung KM , Stella N , Singh S , Mor M , Piomelli D
Ref : Journal of Medicinal Chemistry , 63 :1261 , 2020
Abstract : 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 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 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.
ESTHER : Castelli_2020_J.Med.Chem_63_1261
PubMedSearch : Castelli_2020_J.Med.Chem_63_1261
PubMedID: 31714779

Title : Discovery of potent and reversible monoacylglycerol lipase inhibitors - King_2009_Chem.Biol_16_1045
Author(s) : King AR , Dotsey EY , Lodola A , Jung KM , Ghomian A , Qiu Y , Fu J , Mor M , Piomelli D
Ref : Chemical Biology , 16 :1045 , 2009
Abstract : Monoacylglycerol lipase (MGL) is a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Previous efforts to design MGL inhibitors have focused on chemical scaffolds that irreversibly block the activity of this enzyme. Here, we describe two naturally occurring terpenoids, pristimerin and euphol, which inhibit MGL activity with high potency (median effective concentration, IC(50) = 93 nM and 315 nM, respectively) through a reversible mechanism. Mutational and modeling studies suggest that the two agents occupy a common hydrophobic pocket located within the putative lid domain of MGL, and each reversibly interacts with one of two adjacent cysteine residues (Cys(201) and Cys(208)) flanking such pocket. This previously unrecognized regulatory region might offer a molecular target for potent and reversible inhibitors of MGL.
ESTHER : King_2009_Chem.Biol_16_1045
PubMedSearch : King_2009_Chem.Biol_16_1045
PubMedID: 19875078