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	Structural and energetic insights into the selective interactions of monoacylglycerol lipase with its natural substrate and small-molecule inhibitors
	Chen, Huayou; Sun, Tengyun1; Chen, Hongzhang; Tian, Rui1; Zhang, Tianxi1; Chen, Zhi1; Ni, Zhong1
刊名	MEDICINAL CHEMISTRY RESEARCH
	2014-05-01
卷号	23期号:5页码:2391-2404
关键词	Monoacylglycerol lipase Fatty acid amide hydrolase Inhibitor selectivity Quantum mechanics/molecular mechanics Quantitative structure-selectivity relationship
ISSN号	1054-2523
其他题名	Med. Chem. Res.
中文摘要	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.
英文摘要	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.
WOS标题词	Science & Technology ; Life Sciences & Biomedicine
类目[WOS]	Chemistry, Medicinal
研究领域[WOS]	Pharmacology & Pharmacy
关键词[WOS]	FREE-ENERGIES ; FORCE-FIELD ; FAAH ; PROTEINS ; DOCKING ; BEARING ; DESIGN
收录类别	SCI
原文出处	://WOS:000332153800022
语种	英语
WOS记录号	WOS:000332153800022
公开日期	2014-05-06
内容类型	期刊论文
版本	出版稿
源URL	[http://ir.ipe.ac.cn/handle/122111/8214]
专题	过程工程研究所_研究所（批量导入）
作者单位	1.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
推荐引用方式 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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