The Binding Mechanisms and Inhibitory Effect of Intravenous Anesthetics on AChE In Vitro and In Vivo: Kinetic Analysis and Molecular Docking
Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and β-amyloid (Aβ) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by severa...
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| Veröffentlicht in: | Neurochemical research 2019-09, Vol.44 (9), p.2147-2155 |
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| description | Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and β-amyloid (Aβ) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD. |
| doi_str_mv | 10.1007/s11064-019-02852-y |
| format | Article |
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The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD.</description><identifier>ISSN: 0364-3190</identifier><identifier>EISSN: 1573-6903</identifier><identifier>DOI: 10.1007/s11064-019-02852-y</identifier><identifier>PMID: 31385137</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Acetylcholinesterase ; Acetylcholinesterase - chemistry ; Acetylcholinesterase - metabolism ; Adult ; Alzheimer's disease ; Anesthetics ; Anesthetics, Intravenous - metabolism ; Anesthetics, Intravenous - pharmacology ; Binding ; Biochemistry ; Biomedical and Life Sciences ; Biomedicine ; Catalytic Domain ; Cell Biology ; Cholinesterase Inhibitors - metabolism ; Cholinesterase Inhibitors - pharmacology ; Humans ; Inhibition ; Inhibitors ; Intravenous administration ; Kinetics ; Male ; Medical treatment ; Midazolam ; Midazolam - metabolism ; Midazolam - pharmacology ; Molecular docking ; Molecular Docking Simulation ; Neurochemistry ; Neurodegenerative diseases ; Neurology ; Neurosciences ; Original Paper ; Propofol ; Propofol - metabolism ; Propofol - pharmacology ; Protein Binding ; Thiopental ; Thiopental - metabolism ; Thiopental - pharmacology ; Young Adult ; β-Amyloid</subject><ispartof>Neurochemical research, 2019-09, Vol.44 (9), p.2147-2155</ispartof><rights>Springer Science+Business Media, LLC, part of Springer Nature 2019</rights><rights>Neurochemical Research is a copyright of Springer, (2019). All Rights Reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-b9f75c6ce6ec04240903001ddc8db2105c6d6bee9122d4166affcaeba47583a23</citedby><cites>FETCH-LOGICAL-c441t-b9f75c6ce6ec04240903001ddc8db2105c6d6bee9122d4166affcaeba47583a23</cites><orcidid>0000-0002-4677-8104</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11064-019-02852-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11064-019-02852-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51298</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31385137$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Işık, Mesut</creatorcontrib><title>The Binding Mechanisms and Inhibitory Effect of Intravenous Anesthetics on AChE In Vitro and In Vivo: Kinetic Analysis and Molecular Docking</title><title>Neurochemical research</title><addtitle>Neurochem Res</addtitle><addtitle>Neurochem Res</addtitle><description>Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and β-amyloid (Aβ) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD.</description><subject>Acetylcholinesterase</subject><subject>Acetylcholinesterase - chemistry</subject><subject>Acetylcholinesterase - metabolism</subject><subject>Adult</subject><subject>Alzheimer's disease</subject><subject>Anesthetics</subject><subject>Anesthetics, Intravenous - metabolism</subject><subject>Anesthetics, Intravenous - pharmacology</subject><subject>Binding</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Catalytic Domain</subject><subject>Cell Biology</subject><subject>Cholinesterase Inhibitors - metabolism</subject><subject>Cholinesterase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Intravenous administration</subject><subject>Kinetics</subject><subject>Male</subject><subject>Medical treatment</subject><subject>Midazolam</subject><subject>Midazolam - metabolism</subject><subject>Midazolam - pharmacology</subject><subject>Molecular docking</subject><subject>Molecular Docking Simulation</subject><subject>Neurochemistry</subject><subject>Neurodegenerative diseases</subject><subject>Neurology</subject><subject>Neurosciences</subject><subject>Original Paper</subject><subject>Propofol</subject><subject>Propofol - metabolism</subject><subject>Propofol - pharmacology</subject><subject>Protein Binding</subject><subject>Thiopental</subject><subject>Thiopental - metabolism</subject><subject>Thiopental - pharmacology</subject><subject>Young Adult</subject><subject>β-Amyloid</subject><issn>0364-3190</issn><issn>1573-6903</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kc1u1DAUhS1ERacDL8ACWWLDJtR_-WM3DFOoaMWmsLUc56ZxyditnVTKO_DQvSVDkViwsuLzneMcHUJec_aeM1aeJs5ZoTLG64yJKhfZ_IyseF7KrKiZfE5WTKIsec2OyUlKN4yhTfAX5FhyWeVclivy66oH-tH51vlregm2N96lfaLGt_Tc965xY4gz3XUd2JGGDi_HaO7BhynRjYc09jA6m2jwdLPtd6jTH26M4ZCAH_fhA_3q_COGDjPMyS35l2EAOw0m0k_B_sQfeEmOOjMkeHU41-T72e5q-yW7-Pb5fLu5yKxSfMyauitzW1gowDIlFMO22K1tbdU2gjPU2qIBqLkQreJFYbrOGmiMKvNKGiHX5N2SexvD3YQd9N4lC8NgPGAvLURR1UrWVY7o23_QmzBFbLFQKq8KJNdELJSNIaUInb6Nbm_irDnTj1vpZSuNW-nfW-kZTW8O0VOzh_bJ8mccBOQCJJT8NcS_b_8n9gFzw5_g</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Işık, Mesut</creator><general>Springer US</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-4677-8104</orcidid></search><sort><creationdate>20190901</creationdate><title>The Binding Mechanisms and Inhibitory Effect of Intravenous Anesthetics on AChE In Vitro and In Vivo: Kinetic Analysis and Molecular Docking</title><author>Işık, Mesut</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-b9f75c6ce6ec04240903001ddc8db2105c6d6bee9122d4166affcaeba47583a23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acetylcholinesterase</topic><topic>Acetylcholinesterase - chemistry</topic><topic>Acetylcholinesterase - metabolism</topic><topic>Adult</topic><topic>Alzheimer's disease</topic><topic>Anesthetics</topic><topic>Anesthetics, Intravenous - metabolism</topic><topic>Anesthetics, Intravenous - pharmacology</topic><topic>Binding</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Catalytic Domain</topic><topic>Cell Biology</topic><topic>Cholinesterase Inhibitors - metabolism</topic><topic>Cholinesterase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Intravenous administration</topic><topic>Kinetics</topic><topic>Male</topic><topic>Medical treatment</topic><topic>Midazolam</topic><topic>Midazolam - metabolism</topic><topic>Midazolam - pharmacology</topic><topic>Molecular docking</topic><topic>Molecular Docking Simulation</topic><topic>Neurochemistry</topic><topic>Neurodegenerative diseases</topic><topic>Neurology</topic><topic>Neurosciences</topic><topic>Original Paper</topic><topic>Propofol</topic><topic>Propofol - metabolism</topic><topic>Propofol - pharmacology</topic><topic>Protein Binding</topic><topic>Thiopental</topic><topic>Thiopental - metabolism</topic><topic>Thiopental - pharmacology</topic><topic>Young Adult</topic><topic>β-Amyloid</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Işık, Mesut</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><jtitle>Neurochemical research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Işık, Mesut</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Binding Mechanisms and Inhibitory Effect of Intravenous Anesthetics on AChE In Vitro and In Vivo: Kinetic Analysis and Molecular Docking</atitle><jtitle>Neurochemical research</jtitle><stitle>Neurochem Res</stitle><addtitle>Neurochem Res</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>44</volume><issue>9</issue><spage>2147</spage><epage>2155</epage><pages>2147-2155</pages><issn>0364-3190</issn><eissn>1573-6903</eissn><abstract>Inhibitors of acetylcholinesterase (AChE), which have an important role in the prevention of excessive AChE activity and β-amyloid (Aβ) formation are widely used in the symptomatic treatment of Alzheimer's disease (AD). The inhibitory effect of anesthetic agents on AChE was determined by several approaches, including binding mechanisms, molecular docking and kinetic analysis. Inhibitory effect of intravenous anesthetics on AChE as in vitro and in vivo have been discovered. The midazolam, propofol and thiopental have shown competitive inhibition type (midazolam > propofol > thiopental) and Ki values were found to be 3.96.0 ± 0.1, 5.75 ± 0.12 and 29.65 ± 2.04 µM, respectively. The thiopental and midazolam showed inhibition effect on AChE in vitro, whereas they showed activation effect in vivo when they are combined together. The order of binding of the drugs to the active site of the 4M0E receptor was found to be midazolam > propofol > thiopental. This study on anesthetic agents that are now widely used in surgical applications, have provided a molecular basis for investigating the drug-enzyme interactions mechanism. In addition, the study is important in understanding the molecular mechanism of inhibitors that are effective in the treatment of AD.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>31385137</pmid><doi>10.1007/s11064-019-02852-y</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-4677-8104</orcidid></addata></record> |
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| subjects | Acetylcholinesterase Acetylcholinesterase - chemistry Acetylcholinesterase - metabolism Adult Alzheimer's disease Anesthetics Anesthetics, Intravenous - metabolism Anesthetics, Intravenous - pharmacology Binding Biochemistry Biomedical and Life Sciences Biomedicine Catalytic Domain Cell Biology Cholinesterase Inhibitors - metabolism Cholinesterase Inhibitors - pharmacology Humans Inhibition Inhibitors Intravenous administration Kinetics Male Medical treatment Midazolam Midazolam - metabolism Midazolam - pharmacology Molecular docking Molecular Docking Simulation Neurochemistry Neurodegenerative diseases Neurology Neurosciences Original Paper Propofol Propofol - metabolism Propofol - pharmacology Protein Binding Thiopental Thiopental - metabolism Thiopental - pharmacology Young Adult β-Amyloid |
| title | The Binding Mechanisms and Inhibitory Effect of Intravenous Anesthetics on AChE In Vitro and In Vivo: Kinetic Analysis and Molecular Docking |
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