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Structural and energetic insights into the selective interactions of monoacylglycerol lipase with its natural substrate and small-molecule inhibitors
Alternative TitleMed. Chem. Res.
Chen, Huayou; Sun, Tengyun1; Chen, Hongzhang; Tian, Rui1; Zhang, Tianxi1; Chen, Zhi1; Ni, Zhong1
2014-05-01
Source PublicationMEDICINAL CHEMISTRY RESEARCH
ISSN1054-2523
Volume23Issue:5Pages:2391-2404
AbstractThe monoacylglycerol lipase (MAGL) regulates 2-arachidonoyl glycerol (2-AG) level in the endocannabinoid system (ECS), which is implicated in a number of severe diseases such as cancer and Alzheimer's disease. However, most existing MAGL inhibitors also show additional inhibitory effects on fatty acid amide hydrolase (FAAH), another member of the ECS that degrades the 2-AG analog N-arachidonoyl ethanolamine. Understanding of molecular mechanism and biological implication underlying the specific interactions in MAGL-ligand recognition is thus fundamentally important for the rational design of selective MAGL inhibitors. In the current study, the structural basis and energetic property regarding the binding of several MAGL inhibitors as well as its substrate 2-AG to both the MAGL and FAAH are investigated systematically by integrating molecular docking, quantum mechanics/molecular mechanics analysis, and Poisson-Boltzmann/surface area solvent model. In addition, a novel quantitative structure-selectivity relationship method is proposed to help in the explanation and prediction of inhibitor selectivity between MAGL and FAAH. It is suggested that the selectivity is primarily determined by the size, topology, and property of the rear moiety of inhibitor compounds; a bulky, bifurcated rear is the prerequisite for a inhibitor to have high selectivity for MAGL over FAAH, whereas those dual-type MAGL-FAAH inhibitors should possess a small, rear moiety-the ideal choice is a single aromatic branch occupying this position.; The monoacylglycerol lipase (MAGL) regulates 2-arachidonoyl glycerol (2-AG) level in the endocannabinoid system (ECS), which is implicated in a number of severe diseases such as cancer and Alzheimer's disease. However, most existing MAGL inhibitors also show additional inhibitory effects on fatty acid amide hydrolase (FAAH), another member of the ECS that degrades the 2-AG analog N-arachidonoyl ethanolamine. Understanding of molecular mechanism and biological implication underlying the specific interactions in MAGL-ligand recognition is thus fundamentally important for the rational design of selective MAGL inhibitors. In the current study, the structural basis and energetic property regarding the binding of several MAGL inhibitors as well as its substrate 2-AG to both the MAGL and FAAH are investigated systematically by integrating molecular docking, quantum mechanics/molecular mechanics analysis, and Poisson-Boltzmann/surface area solvent model. In addition, a novel quantitative structure-selectivity relationship method is proposed to help in the explanation and prediction of inhibitor selectivity between MAGL and FAAH. It is suggested that the selectivity is primarily determined by the size, topology, and property of the rear moiety of inhibitor compounds; a bulky, bifurcated rear is the prerequisite for a inhibitor to have high selectivity for MAGL over FAAH, whereas those dual-type MAGL-FAAH inhibitors should possess a small, rear moiety-the ideal choice is a single aromatic branch occupying this position.
KeywordMonoacylglycerol Lipase Fatty Acid Amide Hydrolase Inhibitor Selectivity Quantum Mechanics/molecular Mechanics Quantitative Structure-selectivity Relationship
SubtypeArticle
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
DOI10.1007/s00044-013-0832-9
URL查看原文
Indexed BySCI
Language英语
WOS KeywordFREE-ENERGIES ; FORCE-FIELD ; FAAH ; PROTEINS ; DOCKING ; BEARING ; DESIGN
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000332153800022
Citation statistics
Cited Times:6[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Version出版稿
Identifierhttp://ir.ipe.ac.cn/handle/122111/8214
Collection研究所(批量导入)
Affiliation1.Jiangsu Univ, Inst Life Sci, Zhenjiang 212013, Peoples R China
2.Chinese Acad Sci, Inst Proc Engn, Natl Key Lab Biochem Engn, Beijing 10090, Peoples R China
Recommended Citation
GB/T 7714
Chen, Huayou,Sun, Tengyun,Chen, Hongzhang,et al. Structural and energetic insights into the selective interactions of monoacylglycerol lipase with its natural substrate and small-molecule inhibitors[J]. MEDICINAL CHEMISTRY RESEARCH,2014,23(5):2391-2404.
APA Chen, Huayou.,Sun, Tengyun.,Chen, Hongzhang.,Tian, Rui.,Zhang, Tianxi.,...&Ni, Zhong.(2014).Structural and energetic insights into the selective interactions of monoacylglycerol lipase with its natural substrate and small-molecule inhibitors.MEDICINAL CHEMISTRY RESEARCH,23(5),2391-2404.
MLA Chen, Huayou,et al."Structural and energetic insights into the selective interactions of monoacylglycerol lipase with its natural substrate and small-molecule inhibitors".MEDICINAL CHEMISTRY RESEARCH 23.5(2014):2391-2404.
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