Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development
A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)...
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| Veröffentlicht in: | ChemMedChem 2020-04, Vol.15 (7), p.623-631 |
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| creator | Tiwari, Purushottam B. Chapagain, Prem P. Seddek, Ahmed Annamalai, Thirunavukkarasu Üren, Aykut Tse‐Dinh, Yuk‐Ching |
| description | A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.
Targeting topoisomerase‐DNA covalent complex: This report presents an approach to design functionally important covalent complexes between bacterial topoisomerase and DNA for molecular simulations. This approach is very useful in the development of new antibacterial drugs. Our results demonstrate the suitability of the model and procedures used in this work for computational studies of inhibitors that target topoisomerases. |
| doi_str_mv | 10.1002/cmdc.201900721 |
| format | Article |
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Targeting topoisomerase‐DNA covalent complex: This report presents an approach to design functionally important covalent complexes between bacterial topoisomerase and DNA for molecular simulations. This approach is very useful in the development of new antibacterial drugs. Our results demonstrate the suitability of the model and procedures used in this work for computational studies of inhibitors that target topoisomerases.</description><identifier>ISSN: 1860-7179</identifier><identifier>EISSN: 1860-7187</identifier><identifier>DOI: 10.1002/cmdc.201900721</identifier><identifier>PMID: 32043806</identifier><language>eng</language><publisher>Germany: Wiley Subscription Services, Inc</publisher><subject>Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; Antibacterial drugs ; Antiinfectives and antibacterials ; Antineoplastic drugs ; Antitumor agents ; Computer simulation ; Coordination compounds ; Covalence ; Deoxyribonucleic acid ; DNA ; DNA topoisomerase ; DNA Topoisomerases, Type I - metabolism ; DNA, Bacterial - drug effects ; Drug Development ; Dynamic stability ; E coli ; Escherichia coli - drug effects ; Escherichia coli - metabolism ; MD simulation ; Molecular dynamics ; Molecular Dynamics Simulation ; Surface plasmon resonance ; Topoisomerase I Inhibitors - chemical synthesis ; Topoisomerase I Inhibitors - chemistry ; Topoisomerase I Inhibitors - pharmacology ; Topoisomerase inhibitors ; Topoisomerase-DNA covalent complex</subject><ispartof>ChemMedChem, 2020-04, Vol.15 (7), p.623-631</ispartof><rights>2020 Wiley‐VCH Verlag GmbH & Co. KGaA, Weinheim</rights><rights>2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4681-86f5faec828ba0548236550c598559e055a757ec3193daae0fc370ed9c30a6cb3</citedby><cites>FETCH-LOGICAL-c4681-86f5faec828ba0548236550c598559e055a757ec3193daae0fc370ed9c30a6cb3</cites><orcidid>0000-0002-5616-5176 ; 0000-0002-2033-1216 ; 0000-0002-3140-0723 ; 0000-0002-0999-4975</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fcmdc.201900721$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fcmdc.201900721$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,776,780,881,1411,27903,27904,45553,45554</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32043806$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tiwari, Purushottam B.</creatorcontrib><creatorcontrib>Chapagain, Prem P.</creatorcontrib><creatorcontrib>Seddek, Ahmed</creatorcontrib><creatorcontrib>Annamalai, Thirunavukkarasu</creatorcontrib><creatorcontrib>Üren, Aykut</creatorcontrib><creatorcontrib>Tse‐Dinh, Yuk‐Ching</creatorcontrib><title>Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development</title><title>ChemMedChem</title><addtitle>ChemMedChem</addtitle><description>A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.
Targeting topoisomerase‐DNA covalent complex: This report presents an approach to design functionally important covalent complexes between bacterial topoisomerase and DNA for molecular simulations. This approach is very useful in the development of new antibacterial drugs. Our results demonstrate the suitability of the model and procedures used in this work for computational studies of inhibitors that target topoisomerases.</description><subject>Anti-Bacterial Agents - chemical synthesis</subject><subject>Anti-Bacterial Agents - chemistry</subject><subject>Anti-Bacterial Agents - pharmacology</subject><subject>Antibacterial drugs</subject><subject>Antiinfectives and antibacterials</subject><subject>Antineoplastic drugs</subject><subject>Antitumor agents</subject><subject>Computer simulation</subject><subject>Coordination compounds</subject><subject>Covalence</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA topoisomerase</subject><subject>DNA Topoisomerases, Type I - metabolism</subject><subject>DNA, Bacterial - drug effects</subject><subject>Drug Development</subject><subject>Dynamic stability</subject><subject>E coli</subject><subject>Escherichia coli - drug effects</subject><subject>Escherichia coli - metabolism</subject><subject>MD simulation</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Surface plasmon resonance</subject><subject>Topoisomerase I Inhibitors - chemical synthesis</subject><subject>Topoisomerase I Inhibitors - chemistry</subject><subject>Topoisomerase I Inhibitors - pharmacology</subject><subject>Topoisomerase inhibitors</subject><subject>Topoisomerase-DNA covalent complex</subject><issn>1860-7179</issn><issn>1860-7187</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhq0KRL-49ogscd7tOI5jmwPSku2XVOilnC2vMymukjjY2YX-e1xtCXDiNJbm8TOv9BJyxmDJAIpz1zduWQDTALJgB-SIqQoWkin5an5LfUiOU3oEKEvF1BtyyAsouYLqiLg67GyHw0Tr0I8d_qShpesvK2qHhn6ybsLobUfvwxh8Cj1Gm_ADvcmod3byYUjUD3Q1TH4zw-u4faBr3GEXxj6rT8nr1nYJ377ME_L18uK-vl7c3l3d1KvbhSsrxRaqakVr0alCbSyIUhW8EgKc0EoIjSCElUKi40zzxlqE1nEJ2GjHwVZuw0_Ix7133G56bFw-HW1nxuh7G59MsN78uxn8N_MQdkYyzqVmWfD-RRDD9y2myTyGbRxyZlNwlUNWlVaZWu4pF0NKEdv5AgPzXIp5LsXMpeQP7_7ONeO_W8iA3gM_fIdP_9GZ-vO6_iP_BYDxmj4</recordid><startdate>20200403</startdate><enddate>20200403</enddate><creator>Tiwari, Purushottam B.</creator><creator>Chapagain, Prem P.</creator><creator>Seddek, Ahmed</creator><creator>Annamalai, Thirunavukkarasu</creator><creator>Üren, Aykut</creator><creator>Tse‐Dinh, Yuk‐Ching</creator><general>Wiley Subscription Services, Inc</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>7QO</scope><scope>7TK</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5616-5176</orcidid><orcidid>https://orcid.org/0000-0002-2033-1216</orcidid><orcidid>https://orcid.org/0000-0002-3140-0723</orcidid><orcidid>https://orcid.org/0000-0002-0999-4975</orcidid></search><sort><creationdate>20200403</creationdate><title>Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development</title><author>Tiwari, Purushottam B. ; Chapagain, Prem P. ; Seddek, Ahmed ; Annamalai, Thirunavukkarasu ; Üren, Aykut ; Tse‐Dinh, Yuk‐Ching</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4681-86f5faec828ba0548236550c598559e055a757ec3193daae0fc370ed9c30a6cb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Anti-Bacterial Agents - chemical synthesis</topic><topic>Anti-Bacterial Agents - chemistry</topic><topic>Anti-Bacterial Agents - pharmacology</topic><topic>Antibacterial drugs</topic><topic>Antiinfectives and antibacterials</topic><topic>Antineoplastic drugs</topic><topic>Antitumor agents</topic><topic>Computer simulation</topic><topic>Coordination compounds</topic><topic>Covalence</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA topoisomerase</topic><topic>DNA Topoisomerases, Type I - metabolism</topic><topic>DNA, Bacterial - drug effects</topic><topic>Drug Development</topic><topic>Dynamic stability</topic><topic>E coli</topic><topic>Escherichia coli - drug effects</topic><topic>Escherichia coli - metabolism</topic><topic>MD simulation</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Surface plasmon resonance</topic><topic>Topoisomerase I Inhibitors - chemical synthesis</topic><topic>Topoisomerase I Inhibitors - chemistry</topic><topic>Topoisomerase I Inhibitors - pharmacology</topic><topic>Topoisomerase inhibitors</topic><topic>Topoisomerase-DNA covalent complex</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tiwari, Purushottam B.</creatorcontrib><creatorcontrib>Chapagain, Prem P.</creatorcontrib><creatorcontrib>Seddek, Ahmed</creatorcontrib><creatorcontrib>Annamalai, Thirunavukkarasu</creatorcontrib><creatorcontrib>Üren, Aykut</creatorcontrib><creatorcontrib>Tse‐Dinh, Yuk‐Ching</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>ChemMedChem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tiwari, Purushottam B.</au><au>Chapagain, Prem P.</au><au>Seddek, Ahmed</au><au>Annamalai, Thirunavukkarasu</au><au>Üren, Aykut</au><au>Tse‐Dinh, Yuk‐Ching</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development</atitle><jtitle>ChemMedChem</jtitle><addtitle>ChemMedChem</addtitle><date>2020-04-03</date><risdate>2020</risdate><volume>15</volume><issue>7</issue><spage>623</spage><epage>631</epage><pages>623-631</pages><issn>1860-7179</issn><eissn>1860-7187</eissn><abstract>A topoisomerase‐DNA transient covalent complex can be a druggable target for novel topoisomerase poison inhibitors that represent a new class of antibacterial or anticancer drugs. Herein, we have investigated molecular features of the functionally important Escherichia coli topoisomerase I (EctopoI)‐DNA covalent complex (EctopoIcc) for molecular simulations, which is very useful in the development of new antibacterial drugs. To demonstrate the usefulness of our approach, we used a model small molecule (SM), NSC76027, obtained from virtual screening. We examined the direct binding of NSC76027 to EctopoI as well as inhibition of EctopoI relaxation activity of this SM via experimental techniques. We then performed molecular dynamics (MD) simulations to investigate the dynamics and stability of EctopoIcc and EctopoI‐NSC76027‐DNA ternary complex. Our simulation results show that NSC76027 forms a stable ternary complex with EctopoIcc. EctopoI investigated here also serves as a model system for investigating a complex of topoisomerase and DNA in which DNA is covalently attached to the protein.
Targeting topoisomerase‐DNA covalent complex: This report presents an approach to design functionally important covalent complexes between bacterial topoisomerase and DNA for molecular simulations. This approach is very useful in the development of new antibacterial drugs. Our results demonstrate the suitability of the model and procedures used in this work for computational studies of inhibitors that target topoisomerases.</abstract><cop>Germany</cop><pub>Wiley Subscription Services, Inc</pub><pmid>32043806</pmid><doi>10.1002/cmdc.201900721</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0002-5616-5176</orcidid><orcidid>https://orcid.org/0000-0002-2033-1216</orcidid><orcidid>https://orcid.org/0000-0002-3140-0723</orcidid><orcidid>https://orcid.org/0000-0002-0999-4975</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Anti-Bacterial Agents - chemical synthesis Anti-Bacterial Agents - chemistry Anti-Bacterial Agents - pharmacology Antibacterial drugs Antiinfectives and antibacterials Antineoplastic drugs Antitumor agents Computer simulation Coordination compounds Covalence Deoxyribonucleic acid DNA DNA topoisomerase DNA Topoisomerases, Type I - metabolism DNA, Bacterial - drug effects Drug Development Dynamic stability E coli Escherichia coli - drug effects Escherichia coli - metabolism MD simulation Molecular dynamics Molecular Dynamics Simulation Surface plasmon resonance Topoisomerase I Inhibitors - chemical synthesis Topoisomerase I Inhibitors - chemistry Topoisomerase I Inhibitors - pharmacology Topoisomerase inhibitors Topoisomerase-DNA covalent complex |
| title | Covalent Complex of DNA and Bacterial Topoisomerase: Implications in Antibacterial Drug Development |
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