Discovery of novel reversible monoacylglycerol lipase inhibitors via docking-based virtual screening

Fengmin Xiong; Xiaoyu Ding; Hao Zhang; Xiaomin Luo; Kaixian Chen; Hualiang Jiang; Cheng Luo; Heng Xu

doi:10.1016/j.bmcl.2021.127986

Discovery of novel reversible monoacylglycerol lipase inhibitors via docking-based virtual screening

Bioorg Med Chem Lett. 2021 Jun 1:41:127986. doi: 10.1016/j.bmcl.2021.127986. Epub 2021 Mar 22.

Authors

Fengmin Xiong¹, Xiaoyu Ding², Hao Zhang³, Xiaomin Luo², Kaixian Chen², Hualiang Jiang⁴, Cheng Luo⁵, Heng Xu⁶

Affiliations

¹ School of Pharmacy, Nanchang University, Nanchang 330006, China.
² Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁴ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China.
⁵ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: cluo@simm.ac.cn.
⁶ Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou 310024, China. Electronic address: idaheng@simm.ac.cn.

PMID: 33766770
DOI: 10.1016/j.bmcl.2021.127986

Abstract

Monoacylglycerol lipase (MAGL) is the major enzyme that catalyzes the hydrolysis of monoacylglycerols (MAGs). MAGL is responsible for degrading 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain and specific tissues. The inhibition of MAGL could attenuate the inflammatory response. Here, we report a series of reversible non-covalent MAGL inhibitors via virtual screening combined with biochemical analysis. The hit, DC630-8 showed low-micromolar activity against MAGL in vitro, and exhibited significant anti-inflammatory effects.

Keywords: Inflammation; Inhibitor; Monoacylglycerol lipase; Virtual screening.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Inflammatory Agents / chemical synthesis
Anti-Inflammatory Agents / chemistry
Anti-Inflammatory Agents / pharmacology*
Cytokines / antagonists & inhibitors*
Cytokines / biosynthesis
Dose-Response Relationship, Drug
Drug Discovery*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Lipopolysaccharides / antagonists & inhibitors
Lipopolysaccharides / pharmacology
Mice
Molecular Docking Simulation*
Molecular Structure
Monoacylglycerol Lipases / antagonists & inhibitors*
Monoacylglycerol Lipases / metabolism
RAW 264.7 Cells
RNA, Messenger / antagonists & inhibitors
RNA, Messenger / biosynthesis
Structure-Activity Relationship

Substances

Anti-Inflammatory Agents
Cytokines
Enzyme Inhibitors
Lipopolysaccharides
RNA, Messenger
Monoacylglycerol Lipases