8PTR

COMPLEX CRYSTAL STRUCTURE OF MUTANT HUMAN MONOGLYCERIDE LIPASE WITH COMPOUND 5r

8PTR の概要

• エントリーDOI: 10.2210/pdb8ptr/pdb
• 関連するPDBエントリー: 8PTC
• 分子名称: Monoglyceride lipase, (3~{R},4~{S})-4-(1,3-benzodioxol-5-yl)-1-[1-(benzotriazol-1-ylcarbonyl)piperidin-4-yl]-3-(3-fluorophenyl)azetidin-2-one, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: alpha/beta hydrolase, hydrolase, serine esterase
• 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: 36227.30

構造登録者

Butini, S.,Benz, J.,Grether, U.,Leibrock, L.,Papa, A.,Maramai, S.,Carullo, G.,Federico, S.,Grillo, A.,Di Guglielmo, B.,Lamponi, S.,Gemma, S.,Campiani, G. (登録日: 2023-07-14, 公開日: 2024-01-31, 最終更新日: 2024-10-16)

主引用文献

Butini, S.,Grether, U.,Jung, K.M.,Ligresti, A.,Allara, M.,Postmus, A.G.J.,Maramai, S.,Brogi, S.,Papa, A.,Carullo, G.,Sykes, D.,Veprintsev, D.,Federico, S.,Grillo, A.,Di Guglielmo, B.,Ramunno, A.,Stevens, A.F.,Heer, D.,Lamponi, S.,Gemma, S.,Benz, J.,Di Marzo, V.,van der Stelt, M.,Piomelli, D.,Campiani, G.
Development of Potent and Selective Monoacylglycerol Lipase Inhibitors. SARs, Structural Analysis, and Biological Characterization.
J.Med.Chem., 67:1758-1782, 2024

PubMed Abstract: New potent, selective monoacylglycerol lipase (MAGL) inhibitors based on the azetidin-2-one scaffold ((±)--, (±)--, and (±)--) were developed as irreversible ligands, as demonstrated by enzymatic and crystallographic studies for (±)-, (±)-, and (±)-. X-ray analyses combined with extensive computational studies allowed us to clarify the binding mode of the compounds. was identified as selective for MAGL when compared with other serine hydrolases. Solubility, metabolic stability, cytotoxicity, and absence of mutagenicity were determined for selected analogues. The most promising compounds ((±)-, (±)-, and (±)-) were used for studies in mice, showing a decrease in MAGL activity and increased 2-arachidonoyl--glycerol levels in forebrain tissue. In particular, is characterized by a high eudysmic ratio and (3,4)- is one of the most potent irreversible inhibitors of /MAGL identified thus far. These results suggest that the new MAGL inhibitors have therapeutic potential for different central and peripheral pathologies.

PubMed: 38241614
DOI: 10.1021/acs.jmedchem.3c01278

実験手法

X-RAY DIFFRACTION (1.73 Å)