5ZUN
Crystal structure of human monoacylglycerol lipase in complex with compound 3l
Summary for 5ZUN
| Entry DOI | 10.2210/pdb5zun/pdb |
| Descriptor | Monoglyceride lipase, (4R)-1-(2'-chloro[1,1'-biphenyl]-3-yl)-4-[4-(1,3-thiazole-2-carbonyl)piperazin-1-yl]pyrrolidin-2-one, TETRAETHYLENE GLYCOL, ... (6 entities in total) |
| Functional Keywords | monoacylglycerol lipase, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 34528.46 |
| Authors | Sogabe, S.,Zama, Y.,Lane, W.,Snell, G. (deposition date: 2018-05-08, release date: 2018-10-17, Last modification date: 2023-11-22) |
| Primary citation | Aida, J.,Fushimi, M.,Kusumoto, T.,Sugiyama, H.,Arimura, N.,Ikeda, S.,Sasaki, M.,Sogabe, S.,Aoyama, K.,Koike, T. Design, Synthesis, and Evaluation of Piperazinyl Pyrrolidin-2-ones as a Novel Series of Reversible Monoacylglycerol Lipase Inhibitors J. Med. Chem., 61:9205-9217, 2018 Cited by PubMed Abstract: Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyzes 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, inhibition of MAGL is an attractive therapeutic target for CNS disorders, particularly neurodegenerative diseases. In this study, we report the structure-based drug design of novel piperazinyl pyrrolidin-2-ones starting from our hit compounds 2a and 2b. By enhancing the interaction of the piperazinyl pyrrolidin-2-one core and its substituents with the MAGL enzyme via design modifications, we identified a potent and reversible MAGL inhibitor, compound ( R)-3t. Oral administration of compound ( R)-3t to mice decreased AA levels and elevated 2-AG levels in the brain. PubMed: 30251836DOI: 10.1021/acs.jmedchem.8b00824 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.35 Å) |
Structure validation
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