8PTC

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

Summary for 8PTC

• Entry DOI: 10.2210/pdb8ptc/pdb
• Descriptor: Monoglyceride lipase, 4-[(3~{R},4~{S})-2-oxidanylidene-3,4-diphenyl-azetidin-1-yl]piperidine-1-carbaldehyde, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: alpha/beta hydrolase, hydrolase, serine esterase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35924.06

Authors

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. (deposition date: 2023-07-14, release date: 2024-01-31, Last modification date: 2024-10-23)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.51 Å)