Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency.

ABSTRACT: Inhibition of monoglyceride lipase (MGL), also known as monoacylglycerol lipase (MAGL), has emerged as a promising approach for treating neurological diseases. To gain useful insights in the design of agents with balanced potency and reactivity, we investigated the mechanism of MGL carbamoylation by the reference triazole urea SAR629 (IC₅₀ = 0.2 nM) and two recently described inhibitors featuring a pyrazole (IC₅₀ = 1800 nM) or a 4-cyanopyrazole (IC₅₀ = 8 nM) leaving group (LG), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. Opposite to what was found for substrate 2-arachidonoyl-sn-glycerol (2-AG), covalent modification of MGL by azole ureas is controlled by LG expulsion. Simulations indicated that changes in the electronic st

SUBMITTER: Galvani F 

PROVIDER: S-EPMC9198976 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature