Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1
Introduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimen-tally validate their affi...
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| Veröffentlicht in: | Drug design, development and therapy development and therapy, 2021-01, Vol.15, p.5035-5059 |
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| creator | Bourafai-Aziez, Asma Benabderrahmane, Mohammed Paysant, Hippolyte Weiswald, Louis-Bastien Poulain, Laurent Carlier, Ludovic Ravault, Delphine Jouanne, Marie Coadou, Gael Oulyadi, Hassan Voisin-Chiret, Anne-Sophie Oliveira, Jana Sopkova-de Santos Sebban, Muriel |
| description | Introduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimen-tally validate their affinity toward Mcl-1. Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete character-ization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. Conclusion: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor. |
| doi_str_mv | 10.2147/DDDT.S323077 |
| format | Article |
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Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete character-ization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. Conclusion: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.</description><identifier>ISSN: 1177-8881</identifier><identifier>EISSN: 1177-8881</identifier><identifier>DOI: 10.2147/DDDT.S323077</identifier><identifier>PMID: 34949914</identifier><language>eng</language><publisher>ALBANY: Dove Medical Press Ltd</publisher><subject>Affinity ; Analytical chemistry ; Apoptosis ; Apoptosis Regulatory Proteins - drug effects ; Biological activity ; Cancer therapies ; Chemical Sciences ; Chemistry, Medicinal ; Comparative analysis ; Data analysis ; deferasirox ; Deferasirox - chemistry ; Deferasirox - pharmacology ; docking ; Drug Repositioning ; drug repurposing ; Drugs ; dynamics ; FDA approval ; Gene expression ; Information management ; Inhibitors ; Kinases ; Lenalidomide - chemistry ; Lenalidomide - pharmacology ; Leukemia ; Life Sciences ; Life Sciences & Biomedicine ; Ligands ; Magnetic Resonance Spectroscopy ; mcl-1 ; Mcl-1 protein ; Molecular docking ; Molecular Docking Simulation ; Molecular dynamics ; Molecular Dynamics Simulation ; Molecular Structure ; Multiple myeloma ; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors ; NMR ; Nuclear magnetic resonance ; Original Research ; Oxcarbazepine - chemistry ; Oxcarbazepine - pharmacology ; Pharmacology & Pharmacy ; Proteins ; Risperidone - chemistry ; Risperidone - pharmacology ; Science & Technology ; Three dimensional models ; Torsemide - chemistry ; Torsemide - pharmacology</subject><ispartof>Drug design, development and therapy, 2021-01, Vol.15, p.5035-5059</ispartof><rights>2021 Bourafai-Aziez et al.</rights><rights>COPYRIGHT 2021 Dove Medical Press Limited</rights><rights>2021. This work is licensed under https://creativecommons.org/licenses/by-nc/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2021 Bourafai-Aziez et al. 2021 Bourafai-Aziez et al.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>3</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000732742200001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c610t-537a328af8ea02af7ac30ac40c71a2c5bcb3c97f331fcb53649aed6219021b273</citedby><cites>FETCH-LOGICAL-c610t-537a328af8ea02af7ac30ac40c71a2c5bcb3c97f331fcb53649aed6219021b273</cites><orcidid>0000-0003-0979-6706 ; 0000-0002-7907-1092 ; 0000-0001-5974-7641 ; 0000-0002-0232-387X ; 0000-0002-1849-3312 ; 0000-0002-9128-7881 ; 0000-0002-9036-6561 ; 0000-0002-4829-8120 ; 0000-0001-5813-1482 ; 0000-0001-5564-2244</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688747/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688747/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2115,3863,27929,27930,39263,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34949914$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://normandie-univ.hal.science/hal-03576776$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Bourafai-Aziez, Asma</creatorcontrib><creatorcontrib>Benabderrahmane, Mohammed</creatorcontrib><creatorcontrib>Paysant, Hippolyte</creatorcontrib><creatorcontrib>Weiswald, Louis-Bastien</creatorcontrib><creatorcontrib>Poulain, Laurent</creatorcontrib><creatorcontrib>Carlier, Ludovic</creatorcontrib><creatorcontrib>Ravault, Delphine</creatorcontrib><creatorcontrib>Jouanne, Marie</creatorcontrib><creatorcontrib>Coadou, Gael</creatorcontrib><creatorcontrib>Oulyadi, Hassan</creatorcontrib><creatorcontrib>Voisin-Chiret, Anne-Sophie</creatorcontrib><creatorcontrib>Oliveira, Jana Sopkova-de Santos</creatorcontrib><creatorcontrib>Sebban, Muriel</creatorcontrib><title>Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1</title><title>Drug design, development and therapy</title><addtitle>DRUG DES DEV THER</addtitle><addtitle>Drug Des Devel Ther</addtitle><description>Introduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimen-tally validate their affinity toward Mcl-1. Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete character-ization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. Conclusion: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.</description><subject>Affinity</subject><subject>Analytical chemistry</subject><subject>Apoptosis</subject><subject>Apoptosis Regulatory Proteins - drug effects</subject><subject>Biological activity</subject><subject>Cancer therapies</subject><subject>Chemical Sciences</subject><subject>Chemistry, Medicinal</subject><subject>Comparative analysis</subject><subject>Data analysis</subject><subject>deferasirox</subject><subject>Deferasirox - chemistry</subject><subject>Deferasirox - pharmacology</subject><subject>docking</subject><subject>Drug Repositioning</subject><subject>drug repurposing</subject><subject>Drugs</subject><subject>dynamics</subject><subject>FDA approval</subject><subject>Gene expression</subject><subject>Information management</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Lenalidomide - chemistry</subject><subject>Lenalidomide - pharmacology</subject><subject>Leukemia</subject><subject>Life Sciences</subject><subject>Life Sciences & Biomedicine</subject><subject>Ligands</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>mcl-1</subject><subject>Mcl-1 protein</subject><subject>Molecular docking</subject><subject>Molecular Docking Simulation</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular Structure</subject><subject>Multiple myeloma</subject><subject>Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Original Research</subject><subject>Oxcarbazepine - chemistry</subject><subject>Oxcarbazepine - pharmacology</subject><subject>Pharmacology & Pharmacy</subject><subject>Proteins</subject><subject>Risperidone - chemistry</subject><subject>Risperidone - pharmacology</subject><subject>Science & Technology</subject><subject>Three dimensional models</subject><subject>Torsemide - chemistry</subject><subject>Torsemide - pharmacology</subject><issn>1177-8881</issn><issn>1177-8881</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><sourceid>DOA</sourceid><recordid>eNqNkt2LEzEUxQdR3HX1zWcZEETRqflqMvFBGFp1ixVB1-eQySRtlulkTDLV_e_N2FrbxQfJQ8LN75ycXG6WPYZggiBhr-fz-dXkK0YYMHYnO4eQsaIsS3j36HyWPQjhGgCKKQL3szNMOOEckvPs49wPq_yL7gffu2C71Zt8ro32MljvfuaLbm1rG0Me1zqvumiLqnd9dNGqvFLRbm28yZ3JP6m2gA-ze0a2QT_a7xfZt_fvrmaXxfLzh8WsWhaKQhCLKWYSo1KaUkuApGFSYSAVAYpBidS0VjVWnBmMoVH1FFPCpW4oghwgWCOGL7LFzrdx8lr03m6kvxFOWvG74PxKSJ8StlpADSDlFFCpCSFNXRNZQgoMQryRwNDk9Xbn1Q_1RjdKd9HL9sT09Kaza7FyW1HSsmRkDPNiZ7C-JbuslmKsATxllDG6hYl9vn_Mu--DDlFsbFC6bWWn3RAEopAgzDgbcz29hV67wXeprSMFOCs5Q3-plUyftZ1xKaMaTUVFS44452CMOPkHlVajN1a5Thub6ieCZ0eCtZZtXAfXDtG6LpyCr3ag8i4Er82hAxCIcTrFOJ1iP50Jf3Lc7AP8ZxwTUO6AH7p2JiirO6UPGADpScQIQukE4MxGOSaauaGLSfry_6X4F9tB_Cg</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Bourafai-Aziez, Asma</creator><creator>Benabderrahmane, Mohammed</creator><creator>Paysant, Hippolyte</creator><creator>Weiswald, Louis-Bastien</creator><creator>Poulain, Laurent</creator><creator>Carlier, Ludovic</creator><creator>Ravault, Delphine</creator><creator>Jouanne, Marie</creator><creator>Coadou, Gael</creator><creator>Oulyadi, Hassan</creator><creator>Voisin-Chiret, Anne-Sophie</creator><creator>Oliveira, Jana Sopkova-de Santos</creator><creator>Sebban, Muriel</creator><general>Dove Medical Press Ltd</general><general>Dove Medical Press Limited</general><general>Taylor & Francis Ltd</general><general>Dove Medical Press</general><general>Dove</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</scope><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>7QO</scope><scope>7RV</scope><scope>7XB</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>KB0</scope><scope>M2O</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>1XC</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-0979-6706</orcidid><orcidid>https://orcid.org/0000-0002-7907-1092</orcidid><orcidid>https://orcid.org/0000-0001-5974-7641</orcidid><orcidid>https://orcid.org/0000-0002-0232-387X</orcidid><orcidid>https://orcid.org/0000-0002-1849-3312</orcidid><orcidid>https://orcid.org/0000-0002-9128-7881</orcidid><orcidid>https://orcid.org/0000-0002-9036-6561</orcidid><orcidid>https://orcid.org/0000-0002-4829-8120</orcidid><orcidid>https://orcid.org/0000-0001-5813-1482</orcidid><orcidid>https://orcid.org/0000-0001-5564-2244</orcidid></search><sort><creationdate>20210101</creationdate><title>Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1</title><author>Bourafai-Aziez, Asma ; Benabderrahmane, Mohammed ; Paysant, Hippolyte ; Weiswald, Louis-Bastien ; Poulain, Laurent ; Carlier, Ludovic ; Ravault, Delphine ; Jouanne, Marie ; Coadou, Gael ; Oulyadi, Hassan ; Voisin-Chiret, Anne-Sophie ; Oliveira, Jana Sopkova-de Santos ; Sebban, Muriel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c610t-537a328af8ea02af7ac30ac40c71a2c5bcb3c97f331fcb53649aed6219021b273</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Affinity</topic><topic>Analytical chemistry</topic><topic>Apoptosis</topic><topic>Apoptosis Regulatory Proteins - 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antagonists & inhibitors</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Original Research</topic><topic>Oxcarbazepine - chemistry</topic><topic>Oxcarbazepine - pharmacology</topic><topic>Pharmacology & Pharmacy</topic><topic>Proteins</topic><topic>Risperidone - chemistry</topic><topic>Risperidone - pharmacology</topic><topic>Science & Technology</topic><topic>Three dimensional models</topic><topic>Torsemide - chemistry</topic><topic>Torsemide - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bourafai-Aziez, Asma</creatorcontrib><creatorcontrib>Benabderrahmane, Mohammed</creatorcontrib><creatorcontrib>Paysant, Hippolyte</creatorcontrib><creatorcontrib>Weiswald, Louis-Bastien</creatorcontrib><creatorcontrib>Poulain, Laurent</creatorcontrib><creatorcontrib>Carlier, Ludovic</creatorcontrib><creatorcontrib>Ravault, Delphine</creatorcontrib><creatorcontrib>Jouanne, Marie</creatorcontrib><creatorcontrib>Coadou, Gael</creatorcontrib><creatorcontrib>Oulyadi, Hassan</creatorcontrib><creatorcontrib>Voisin-Chiret, Anne-Sophie</creatorcontrib><creatorcontrib>Oliveira, Jana Sopkova-de Santos</creatorcontrib><creatorcontrib>Sebban, Muriel</creatorcontrib><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Web of Science - 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Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Drug design, development and therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bourafai-Aziez, Asma</au><au>Benabderrahmane, Mohammed</au><au>Paysant, Hippolyte</au><au>Weiswald, Louis-Bastien</au><au>Poulain, Laurent</au><au>Carlier, Ludovic</au><au>Ravault, Delphine</au><au>Jouanne, Marie</au><au>Coadou, Gael</au><au>Oulyadi, Hassan</au><au>Voisin-Chiret, Anne-Sophie</au><au>Oliveira, Jana Sopkova-de Santos</au><au>Sebban, Muriel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1</atitle><jtitle>Drug design, development and therapy</jtitle><stitle>DRUG DES DEV THER</stitle><addtitle>Drug Des Devel Ther</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>15</volume><spage>5035</spage><epage>5059</epage><pages>5035-5059</pages><issn>1177-8881</issn><eissn>1177-8881</eissn><abstract>Introduction: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimen-tally validate their affinity toward Mcl-1. Results: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete character-ization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. Conclusion: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.</abstract><cop>ALBANY</cop><pub>Dove Medical Press Ltd</pub><pmid>34949914</pmid><doi>10.2147/DDDT.S323077</doi><tpages>25</tpages><orcidid>https://orcid.org/0000-0003-0979-6706</orcidid><orcidid>https://orcid.org/0000-0002-7907-1092</orcidid><orcidid>https://orcid.org/0000-0001-5974-7641</orcidid><orcidid>https://orcid.org/0000-0002-0232-387X</orcidid><orcidid>https://orcid.org/0000-0002-1849-3312</orcidid><orcidid>https://orcid.org/0000-0002-9128-7881</orcidid><orcidid>https://orcid.org/0000-0002-9036-6561</orcidid><orcidid>https://orcid.org/0000-0002-4829-8120</orcidid><orcidid>https://orcid.org/0000-0001-5813-1482</orcidid><orcidid>https://orcid.org/0000-0001-5564-2244</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1177-8881 |
| ispartof | Drug design, development and therapy, 2021-01, Vol.15, p.5035-5059 |
| issn | 1177-8881 1177-8881 |
| language | eng |
| recordid | cdi_pubmed_primary_34949914 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Dove Press Free; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Web of Science - Science Citation Index Expanded - 2021<img src="https://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" />; Access via Taylor & Francis (Open Access Collection); PubMed Central |
| subjects | Affinity Analytical chemistry Apoptosis Apoptosis Regulatory Proteins - drug effects Biological activity Cancer therapies Chemical Sciences Chemistry, Medicinal Comparative analysis Data analysis deferasirox Deferasirox - chemistry Deferasirox - pharmacology docking Drug Repositioning drug repurposing Drugs dynamics FDA approval Gene expression Information management Inhibitors Kinases Lenalidomide - chemistry Lenalidomide - pharmacology Leukemia Life Sciences Life Sciences & Biomedicine Ligands Magnetic Resonance Spectroscopy mcl-1 Mcl-1 protein Molecular docking Molecular Docking Simulation Molecular dynamics Molecular Dynamics Simulation Molecular Structure Multiple myeloma Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors NMR Nuclear magnetic resonance Original Research Oxcarbazepine - chemistry Oxcarbazepine - pharmacology Pharmacology & Pharmacy Proteins Risperidone - chemistry Risperidone - pharmacology Science & Technology Three dimensional models Torsemide - chemistry Torsemide - pharmacology |
| title | Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1 |
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