Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers
The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast canc...
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| Veröffentlicht in: | Molecular diversity 2016-05, Vol.20 (2), p.521-535 |
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| creator | Anantaraju, Hasitha Shilpa Battu, Madhu Babu Viswanadha, Srikant Sriram, Dharmarajan Yogeeswari, Perumal |
| description | The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast cancers (TPBC & TNBC). The crystal structure of CatD at 2.5 Å resolution (PDB: 1LYB), which was complexed with Pepstatin A, was selected for computer-aided molecular modeling. The methods used in our study were pharmacophore modeling and molecular docking. Virtual screening was performed to identify small molecules from an in-house database and a large commercial chemical library. Cytotoxicity studies were performed on human normal cell line HEK293T and growth inhibition studies on breast adenocarcinoma cell lines, namely MCF-7, MDA-MB-231, SK-BR-3, and MDA-MB-468. Furthermore, RT-PCR analysis, in vitro enzyme assay, and cell cycle analysis ascertained the validity of the selected molecules. A set of 28 molecules was subjected to an in vitro fluorescence-based inhibitory activity assay, and among them six molecules exhibited
>
50 % inhibition at
25
μ
M
. These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules
1
and
17
showed single-digit micromolar
GI
50
values against MCF-7 and MDA-MB-231 cell lines. |
| doi_str_mv | 10.1007/s11030-015-9645-8 |
| format | Article |
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>
50 % inhibition at
25
μ
M
. These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules
1
and
17
showed single-digit micromolar
GI
50
values against MCF-7 and MDA-MB-231 cell lines.</description><identifier>ISSN: 1381-1991</identifier><identifier>EISSN: 1573-501X</identifier><identifier>DOI: 10.1007/s11030-015-9645-8</identifier><identifier>PMID: 26563150</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Biochemistry ; Biomedical and Life Sciences ; Breast cancer ; Cathepsin D - antagonists & inhibitors ; Cathepsin D - chemistry ; Cathepsin D - genetics ; Cathepsin D - metabolism ; Cell Cycle Checkpoints - drug effects ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Crystal structure ; Drug Screening Assays, Antitumor ; Gene Expression Regulation, Neoplastic - drug effects ; Humans ; Hydrogen-Ion Concentration ; Life Sciences ; Lysosomes - drug effects ; Lysosomes - metabolism ; Molecular Docking Simulation ; Molecules ; Organic Chemistry ; Original Article ; Pharmaceutical sciences ; Pharmacy ; Polymer Sciences ; Protease Inhibitors - chemistry ; Protease Inhibitors - metabolism ; Protease Inhibitors - pharmacology ; Protein Conformation ; Proteins ; Triple Negative Breast Neoplasms - pathology ; Tumor Microenvironment - drug effects</subject><ispartof>Molecular diversity, 2016-05, Vol.20 (2), p.521-535</ispartof><rights>Springer International Publishing Switzerland 2015</rights><rights>Springer International Publishing Switzerland 2016</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c372t-f98897af9fdadb708b156a03175638a29529ded70f52a58b10a99af00f477d713</citedby><cites>FETCH-LOGICAL-c372t-f98897af9fdadb708b156a03175638a29529ded70f52a58b10a99af00f477d713</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s11030-015-9645-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s11030-015-9645-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26563150$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Anantaraju, Hasitha Shilpa</creatorcontrib><creatorcontrib>Battu, Madhu Babu</creatorcontrib><creatorcontrib>Viswanadha, Srikant</creatorcontrib><creatorcontrib>Sriram, Dharmarajan</creatorcontrib><creatorcontrib>Yogeeswari, Perumal</creatorcontrib><title>Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers</title><title>Molecular diversity</title><addtitle>Mol Divers</addtitle><addtitle>Mol Divers</addtitle><description>The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast cancers (TPBC & TNBC). The crystal structure of CatD at 2.5 Å resolution (PDB: 1LYB), which was complexed with Pepstatin A, was selected for computer-aided molecular modeling. The methods used in our study were pharmacophore modeling and molecular docking. Virtual screening was performed to identify small molecules from an in-house database and a large commercial chemical library. Cytotoxicity studies were performed on human normal cell line HEK293T and growth inhibition studies on breast adenocarcinoma cell lines, namely MCF-7, MDA-MB-231, SK-BR-3, and MDA-MB-468. Furthermore, RT-PCR analysis, in vitro enzyme assay, and cell cycle analysis ascertained the validity of the selected molecules. A set of 28 molecules was subjected to an in vitro fluorescence-based inhibitory activity assay, and among them six molecules exhibited
>
50 % inhibition at
25
μ
M
. These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules
1
and
17
showed single-digit micromolar
GI
50
values against MCF-7 and MDA-MB-231 cell lines.</description><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Breast cancer</subject><subject>Cathepsin D - antagonists & inhibitors</subject><subject>Cathepsin D - chemistry</subject><subject>Cathepsin D - genetics</subject><subject>Cathepsin D - metabolism</subject><subject>Cell Cycle Checkpoints - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Crystal structure</subject><subject>Drug Screening Assays, Antitumor</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Life Sciences</subject><subject>Lysosomes - drug effects</subject><subject>Lysosomes - metabolism</subject><subject>Molecular Docking Simulation</subject><subject>Molecules</subject><subject>Organic Chemistry</subject><subject>Original Article</subject><subject>Pharmaceutical sciences</subject><subject>Pharmacy</subject><subject>Polymer Sciences</subject><subject>Protease Inhibitors - chemistry</subject><subject>Protease Inhibitors - metabolism</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Triple Negative Breast Neoplasms - pathology</subject><subject>Tumor Microenvironment - drug effects</subject><issn>1381-1991</issn><issn>1573-501X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</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>eNp1kc9u1DAQxiMEoqXwAFyQJS5cDJ5kHdvc0JZ_UhEXkLhZk2S8dcnawXYq8U48JG53QYDEyfbM7_tmrK9pHoN4DkKoFxlAdIILkNz0G8n1neYUpOq4FPDlbr13GjgYAyfNg5yvhKgq6O43J20v-w6kOG1-bLFc0pJ9YOfMh0s_-BJTZpjZEguF4nFmlUi40Fr8mJmLiQ2JMBc2YhgpsVJfZV_Zl-xDnGlcZ0xsiuNXH3YMw8QGH-ka5xWLj4HhDn2o6pL8MhMPtKv1a7olj7UlZn9b-2tQftjcczhnenQ8z5rPb15_2r7jFx_fvt--uuBjp9rCndHaKHTGTTgNSugBZI-iA1V_rbE1sjUTTUo42aKsXYHGoBPCbZSaFHRnzbOD75Lit5VysXufR5pnDBTXbEFpIaHtjaro03_Qq7imULerlDIKQMtNpeBAjSnmnMjZJfk9pu8WhL2J0h6itDVKexOl1VXz5Oi8Dnuafit-ZVeB9gDk2go7Sn-M_q_rT_EBrRE</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Anantaraju, Hasitha Shilpa</creator><creator>Battu, Madhu Babu</creator><creator>Viswanadha, Srikant</creator><creator>Sriram, Dharmarajan</creator><creator>Yogeeswari, Perumal</creator><general>Springer International Publishing</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>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope></search><sort><creationdate>20160501</creationdate><title>Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers</title><author>Anantaraju, Hasitha Shilpa ; Battu, Madhu Babu ; Viswanadha, Srikant ; Sriram, Dharmarajan ; Yogeeswari, Perumal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c372t-f98897af9fdadb708b156a03175638a29529ded70f52a58b10a99af00f477d713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Breast cancer</topic><topic>Cathepsin D - antagonists & inhibitors</topic><topic>Cathepsin D - chemistry</topic><topic>Cathepsin D - genetics</topic><topic>Cathepsin D - metabolism</topic><topic>Cell Cycle Checkpoints - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Crystal structure</topic><topic>Drug Screening Assays, Antitumor</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Life Sciences</topic><topic>Lysosomes - drug effects</topic><topic>Lysosomes - metabolism</topic><topic>Molecular Docking Simulation</topic><topic>Molecules</topic><topic>Organic Chemistry</topic><topic>Original Article</topic><topic>Pharmaceutical sciences</topic><topic>Pharmacy</topic><topic>Polymer Sciences</topic><topic>Protease Inhibitors - chemistry</topic><topic>Protease Inhibitors - metabolism</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Protein Conformation</topic><topic>Proteins</topic><topic>Triple Negative Breast Neoplasms - pathology</topic><topic>Tumor Microenvironment - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Anantaraju, Hasitha Shilpa</creatorcontrib><creatorcontrib>Battu, Madhu Babu</creatorcontrib><creatorcontrib>Viswanadha, Srikant</creatorcontrib><creatorcontrib>Sriram, Dharmarajan</creatorcontrib><creatorcontrib>Yogeeswari, Perumal</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</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>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular diversity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Anantaraju, Hasitha Shilpa</au><au>Battu, Madhu Babu</au><au>Viswanadha, Srikant</au><au>Sriram, Dharmarajan</au><au>Yogeeswari, Perumal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers</atitle><jtitle>Molecular diversity</jtitle><stitle>Mol Divers</stitle><addtitle>Mol Divers</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>20</volume><issue>2</issue><spage>521</spage><epage>535</epage><pages>521-535</pages><issn>1381-1991</issn><eissn>1573-501X</eissn><abstract>The main aim of this study was to discover small molecule inhibitors against Cathepsin D (CatD) (EC.3.4.23.5), a clinically proven prognostic marker for breast cancer, and to explore the mechanisms by which CatD could be a useful therapeutic target for triple-positive and triple-negative breast cancers (TPBC & TNBC). The crystal structure of CatD at 2.5 Å resolution (PDB: 1LYB), which was complexed with Pepstatin A, was selected for computer-aided molecular modeling. The methods used in our study were pharmacophore modeling and molecular docking. Virtual screening was performed to identify small molecules from an in-house database and a large commercial chemical library. Cytotoxicity studies were performed on human normal cell line HEK293T and growth inhibition studies on breast adenocarcinoma cell lines, namely MCF-7, MDA-MB-231, SK-BR-3, and MDA-MB-468. Furthermore, RT-PCR analysis, in vitro enzyme assay, and cell cycle analysis ascertained the validity of the selected molecules. A set of 28 molecules was subjected to an in vitro fluorescence-based inhibitory activity assay, and among them six molecules exhibited
>
50 % inhibition at
25
μ
M
. These molecules also exhibited good growth inhibition against TPBC and TNBC cancer types. Among them, molecules
1
and
17
showed single-digit micromolar
GI
50
values against MCF-7 and MDA-MB-231 cell lines.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>26563150</pmid><doi>10.1007/s11030-015-9645-8</doi><tpages>15</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1381-1991 |
| ispartof | Molecular diversity, 2016-05, Vol.20 (2), p.521-535 |
| issn | 1381-1991 1573-501X |
| language | eng |
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| subjects | Biochemistry Biomedical and Life Sciences Breast cancer Cathepsin D - antagonists & inhibitors Cathepsin D - chemistry Cathepsin D - genetics Cathepsin D - metabolism Cell Cycle Checkpoints - drug effects Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Crystal structure Drug Screening Assays, Antitumor Gene Expression Regulation, Neoplastic - drug effects Humans Hydrogen-Ion Concentration Life Sciences Lysosomes - drug effects Lysosomes - metabolism Molecular Docking Simulation Molecules Organic Chemistry Original Article Pharmaceutical sciences Pharmacy Polymer Sciences Protease Inhibitors - chemistry Protease Inhibitors - metabolism Protease Inhibitors - pharmacology Protein Conformation Proteins Triple Negative Breast Neoplasms - pathology Tumor Microenvironment - drug effects |
| title | Cathepsin D inhibitors as potential therapeutics for breast cancer treatment: Molecular docking and bioevaluation against triple-negative and triple-positive breast cancers |
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