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In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues

Shiyan Chen, Karl Austin-Muttitt, Linghua Harris Zhang, Jonathan Mullins Orcid Logo, Aik Jiang Lau

Journal of Pharmacology and Experimental Therapeutics, Volume: 371, Issue: 1, Pages: 75 - 86

Swansea University Author: Jonathan Mullins Orcid Logo

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DOI (Published version): 10.1124/jpet.119.259267

Abstract

Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective oestrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, dif...

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Published in: Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565 1521-0103
Published: United States ASPET 2019
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URI: https://cronfa.swan.ac.uk/Record/cronfa51722
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2019-09-20T16:18:25.4736989</datestamp><bib-version>v2</bib-version><id>51722</id><entry>2019-09-06</entry><title>In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues</title><swanseaauthors><author><sid>4cf2dddedbe1dacb506ec925fdbd5b40</sid><ORCID>0000-0003-0144-2962</ORCID><firstname>Jonathan</firstname><surname>Mullins</surname><name>Jonathan Mullins</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2019-09-06</date><deptcode>BMS</deptcode><abstract>Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective oestrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Tamoxifen, raloxifene, and nafoxidine are selective oestrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogues was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank-order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene &gt; bazedoxifene ~ lasofoxifene &gt; tamoxifen &gt; acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular docking analyses provide new insights into the interaction between SERMs and AOX1. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals.</abstract><type>Journal Article</type><journal>Journal of Pharmacology and Experimental Therapeutics</journal><volume>371</volume><journalNumber>1</journalNumber><paginationStart>75</paginationStart><paginationEnd>86</paginationEnd><publisher>ASPET</publisher><placeOfPublication>United States</placeOfPublication><issnPrint>0022-3565</issnPrint><issnElectronic>1521-0103</issnElectronic><keywords>drug metabolism; enzyme kinetics; estrone; inhibition</keywords><publishedDay>9</publishedDay><publishedMonth>7</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-07-09</publishedDate><doi>10.1124/jpet.119.259267</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><lastEdited>2019-09-20T16:18:25.4736989</lastEdited><Created>2019-09-06T16:21:48.0875669</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Shiyan</firstname><surname>Chen</surname><order>1</order></author><author><firstname>Karl</firstname><surname>Austin-Muttitt</surname><order>2</order></author><author><firstname>Linghua Harris</firstname><surname>Zhang</surname><order>3</order></author><author><firstname>Jonathan</firstname><surname>Mullins</surname><orcid>0000-0003-0144-2962</orcid><order>4</order></author><author><firstname>Aik Jiang</firstname><surname>Lau</surname><order>5</order></author></authors><documents/><OutputDurs/></rfc1807>
spelling 2019-09-20T16:18:25.4736989 v2 51722 2019-09-06 In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues 4cf2dddedbe1dacb506ec925fdbd5b40 0000-0003-0144-2962 Jonathan Mullins Jonathan Mullins true false 2019-09-06 BMS Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective oestrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Tamoxifen, raloxifene, and nafoxidine are selective oestrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogues was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank-order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene > bazedoxifene ~ lasofoxifene > tamoxifen > acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular docking analyses provide new insights into the interaction between SERMs and AOX1. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals. Journal Article Journal of Pharmacology and Experimental Therapeutics 371 1 75 86 ASPET United States 0022-3565 1521-0103 drug metabolism; enzyme kinetics; estrone; inhibition 9 7 2019 2019-07-09 10.1124/jpet.119.259267 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2019-09-20T16:18:25.4736989 2019-09-06T16:21:48.0875669 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Shiyan Chen 1 Karl Austin-Muttitt 2 Linghua Harris Zhang 3 Jonathan Mullins 0000-0003-0144-2962 4 Aik Jiang Lau 5
title In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
spellingShingle In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
Jonathan Mullins
title_short In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
title_full In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
title_fullStr In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
title_full_unstemmed In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
title_sort In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues
author_id_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40
author_id_fullname_str_mv 4cf2dddedbe1dacb506ec925fdbd5b40_***_Jonathan Mullins
author Jonathan Mullins
author2 Shiyan Chen
Karl Austin-Muttitt
Linghua Harris Zhang
Jonathan Mullins
Aik Jiang Lau
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container_start_page 75
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institution Swansea University
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doi_str_mv 10.1124/jpet.119.259267
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective oestrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Tamoxifen, raloxifene, and nafoxidine are selective oestrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogues was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank-order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene > bazedoxifene ~ lasofoxifene > tamoxifen > acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular docking analyses provide new insights into the interaction between SERMs and AOX1. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals.
published_date 2019-07-09T04:03:44Z
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score 11.03559

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