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In this paper, molecular docking and molecular dynamics simulations, combined with binding free energy calculation, were employed to investigate the inhibitory mechanism and binding modes of four aryl formyl piperidine derivative inhibitors with different 1-substituents to MAGL. The results showed that in the four systems, the main four regions where the enzyme bound to the inhibitor included around the head aromatic ring, the head carbonyl oxygen, the tail amide bond, and the tail benzene ring. The significant conformational changes in the more flexible lid domain of the enzyme were caused by 1-substituted group differences of inhibitors and resulted in different degrees of flipping in the tail of the inhibitor. The flipping led to a different direction of the tail amide bond and made a greater variation in its interaction with some of the charged residues in the enzyme, which further contributed to a different swing of the tail benzene ring. If the swing is large enough, it can weaken the binding strength of the head carbonyl oxygen to its nearby residues, and even the whole inhibitor with the enzyme so that the inhibition decreases.<\/jats:p>","DOI":"10.3390\/molecules27217512","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T04:00:51Z","timestamp":1667534451000},"page":"7512","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Insight into the Inhibitory Mechanism of Aryl Formyl Piperidine Derivatives on Monoacylglycerol Lipase through Molecular Dynamics Simulations"],"prefix":"10.3390","volume":"27","author":[{"given":"Chang","family":"Liu","sequence":"first","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Guan","sequence":"additional","affiliation":[{"name":"College of Biology and Food Engineering, Jilin Engineering Normal University, Changchun 130052, China"},{"name":"Key Laboratory of Molecular Nutrition at Universities of Jilin Province, Changchun 130052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9183-7257","authenticated-orcid":false,"given":"Jingwen","family":"E","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianan","family":"Ju","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104532","DOI":"10.1016\/j.neubiorev.2022.104532","article-title":"Sleep disorders and non-sleep circadian disorders predict depression: A systematic review and meta-analysis of longitudinal studies","volume":"134","author":"Zhang","year":"2022","journal-title":"Neurosci. 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