8AQF

CRYSTAL STRUCTURE OF HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND LEI-515

8AQF の概要

• エントリーDOI: 10.2210/pdb8aqf/pdb
• 分子名称: 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)
• 機能のキーワード: monoacylglycerol lipase, magl, inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35996.96

構造登録者

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. (登録日: 2022-08-12, 公開日: 2023-08-23, 最終更新日: 2026-03-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.55 Å)