8AQF

CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND LEI-515

Summary for 8AQF

• Entry DOI: 10.2210/pdb8aqf/pdb
• Descriptor: Monoglyceride lipase, 1-[(~{R})-[2-chloranyl-4-[(2~{S},3~{S})-4-(3-chlorophenyl)-2,3-dimethyl-piperazin-1-yl]carbonyl-phenyl]sulfinyl]-3,3-bis(fluoranyl)pentan-2-one (3 entities in total)
• Functional Keywords: monoacylglycerol lipase, magl, inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35996.96

Authors

Jiang, M.,Huizenga, M.,Wirt, J.,Paloczi, J.,Amedi, A.,van der Berg, R.,Benz, J.,Collin, L.,Deng, H.,Driever, W.,Florea, B.,Grether, U.,Janssen, A.,Heitman, L.,Lam, T.W.,Mohr, F.,Pavlovic, A.,Ruf, I.,Rutjes, H.,Stevens, F.,van der Vliet, D.,van der Wel, T.,Wittwer, M.,Boeckel, C.,Pacher, P.,Hohmann, A.,van der Stelt, M. (deposition date: 2022-08-12, release date: 2023-08-23, Last modification date: 2025-03-12)

Primary citation

Jiang, M.,Huizenga, M.C.W.,Wirt, J.L.,Paloczi, J.,Amedi, A.,van den Berg, R.J.B.H.N.,Benz, J.,Collin, L.,Deng, H.,Di, X.,Driever, W.F.,Florea, B.I.,Grether, U.,Janssen, A.P.A.,Hankemeier, T.,Heitman, L.H.,Lam, T.W.,Mohr, F.,Pavlovic, A.,Ruf, I.,van den Hurk, H.,Stevens, A.F.,van der Vliet, D.,van der Wel, T.,Wittwer, M.B.,van Boeckel, C.A.A.,Pacher, P.,Hohmann, A.G.,van der Stelt, M.
A monoacylglycerol lipase inhibitor showing therapeutic efficacy in mice without central side effects or dependence.
Nat Commun, 14:8039-8039, 2023

PubMed Abstract: Monoacylglycerol lipase (MAGL) regulates endocannabinoid 2-arachidonoylglycerol (2-AG) and eicosanoid signalling. MAGL inhibition provides therapeutic opportunities but clinical potential is limited by central nervous system (CNS)-mediated side effects. Here, we report the discovery of LEI-515, a peripherally restricted, reversible MAGL inhibitor, using high throughput screening and a medicinal chemistry programme. LEI-515 increased 2-AG levels in peripheral organs, but not mouse brain. LEI-515 attenuated liver necrosis, oxidative stress and inflammation in a CCl-induced acute liver injury model. LEI-515 suppressed chemotherapy-induced neuropathic nociception in mice without inducing cardinal signs of CB activation. Antinociceptive efficacy of LEI-515 was blocked by CB, but not CB, antagonists. The CB antagonist rimonabant precipitated signs of physical dependence in mice treated chronically with a global MAGL inhibitor (JZL184), and an orthosteric cannabinoid agonist (WIN55,212-2), but not with LEI-515. Our data support targeting peripheral MAGL as a promising therapeutic strategy for developing safe and effective anti-inflammatory and analgesic agents.

PubMed: 38052772
DOI: 10.1038/s41467-023-43606-3

Experimental method

X-RAY DIFFRACTION (1.55 Å)