Discovery of potent and reversible monoacylglycerol lipase inhibitors.
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.
King
Alvin R
AR
Department of Pharmacology, University of California Irvine, Irvine, CA 92697, USA.
Dotsey
Emmanuel Y
EY
Lodola
Alessio
A
Jung
Kwang Mook
KM
Ghomian
Azar
A
Qiu
Yan
Y
Fu
Jin
J
Mor
Marco
M
Piomelli
Daniele
D
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D056004:Molecular Dynamics Simulation; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D053978:Pentacyclic Triterpenes; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D007810:Lanosterol; C062557:euphol; D008994:Monoacylglycerol Lipases; C050414:celastrol; D005990:Glycerol