Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach
As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS...
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| Veröffentlicht in: | International journal of biological macromolecules 2023-07, Vol.242 (Pt 1), p.124443, Article 124443 |
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| container_title | International journal of biological macromolecules |
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| creator | Dinesh, T.V. Malgija, Beutline Ponraj, Mano Ranjana Muralakar, Pavankumar Thathapudi, Jesse Joel Kandasamy, Ruckmani Alagarmalai, Jeyasankar Balakrishnan, Anna Benedict Ramar, Perumal Samy James, Jannet Vennila Bhagavathsingh, Jebasingh |
| description | As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and Mpro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with Mpro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for Mpro and RdRp. |
| doi_str_mv | 10.1016/j.ijbiomac.2023.124443 |
| format | Article |
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Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and Mpro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with Mpro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for Mpro and RdRp.</description><identifier>ISSN: 0141-8130</identifier><identifier>ISSN: 1879-0003</identifier><identifier>EISSN: 1879-0003</identifier><identifier>DOI: 10.1016/j.ijbiomac.2023.124443</identifier><identifier>PMID: 37148943</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Antiviral Agents - chemistry ; Corona virus ; Covalent docking ; COVID-19 ; COVID-19 Drug Treatment ; Humans ; Main protease ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular dynamics simulations ; Molecular modelling ; Pyrimidine based remdesivir analogues ; Pyrimidines - pharmacology ; RNA-dependent DNA polymerase ; RNA-Dependent RNA Polymerase - genetics ; SARS CoV-2 ; SARS-CoV-2 - metabolism</subject><ispartof>International journal of biological macromolecules, 2023-07, Vol.242 (Pt 1), p.124443, Article 124443</ispartof><rights>2023 Elsevier B.V.</rights><rights>Copyright © 2023 Elsevier B.V. All rights reserved.</rights><rights>2023 Published by Elsevier B.V. 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c419t-d8dc9a5d9fcbd9f12c1badcb8879dac8f674269dee08cdf034803aadbafda0ba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ijbiomac.2023.124443$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,314,780,784,885,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37148943$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dinesh, T.V.</creatorcontrib><creatorcontrib>Malgija, Beutline</creatorcontrib><creatorcontrib>Ponraj, Mano Ranjana</creatorcontrib><creatorcontrib>Muralakar, Pavankumar</creatorcontrib><creatorcontrib>Thathapudi, Jesse Joel</creatorcontrib><creatorcontrib>Kandasamy, Ruckmani</creatorcontrib><creatorcontrib>Alagarmalai, Jeyasankar</creatorcontrib><creatorcontrib>Balakrishnan, Anna Benedict</creatorcontrib><creatorcontrib>Ramar, Perumal Samy</creatorcontrib><creatorcontrib>James, Jannet Vennila</creatorcontrib><creatorcontrib>Bhagavathsingh, Jebasingh</creatorcontrib><title>Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach</title><title>International journal of biological macromolecules</title><addtitle>Int J Biol Macromol</addtitle><description>As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. Herein, we designed pyrimidine based nucleotides and assessed for the binding capability with SARS-CoV-2 viral replication targets of nsp12 RNA-dependent RNA polymerase and Mpro main protease. Molecular docking studies showed all the designed compounds to possess good binding affinity, with a few compounds which outperforms the control drug remdesivir GS-5743 and its active form GS-441524. Further molecular dynamics simulation studies confirmed their stability and preservation of the non-covalent interactions. Based on the present findings Ligand2-BzV_0Tyr, ligand3-BzV_0Ura, and ligand5-EeV_0Tyr showed good binding affinity with Mpro, whereas, ligand1-BzV_0Cys and Ligand2-BzV_0Tyr showed good binding affinity with RdRp, thus could act as potential lead compounds against SARS-CoV-2, which needs further validation studies. In particular, Ligand2-BzV_0Tyr could be more beneficial candidate with the dual target specificity for Mpro and RdRp.</description><subject>Antiviral Agents - chemistry</subject><subject>Corona virus</subject><subject>Covalent docking</subject><subject>COVID-19</subject><subject>COVID-19 Drug Treatment</subject><subject>Humans</subject><subject>Main protease</subject><subject>Molecular Docking Simulation</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular dynamics simulations</subject><subject>Molecular modelling</subject><subject>Pyrimidine based remdesivir analogues</subject><subject>Pyrimidines - pharmacology</subject><subject>RNA-dependent DNA polymerase</subject><subject>RNA-Dependent RNA Polymerase - genetics</subject><subject>SARS CoV-2</subject><subject>SARS-CoV-2 - metabolism</subject><issn>0141-8130</issn><issn>1879-0003</issn><issn>1879-0003</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFUctu2zAQJIoGjeP2FwIee5FDSrJM9dIa7hMIUKBpeyVW5MpeQxJVknJh9OfDwEmQnHpZAsvZ2Z0Zxi6lWEghq6v9gvYNuR7MIhd5sZB5WZbFCzaTalVnQojiJZsJWcpMyUKcs4sQ9qlbLaV6xc6LlSxVXRYz9u8jBtoO3LV8cAfs-Hj01JOlAXkDAS332NuEOZDnMEDnthMG_pfijtsJOh7BbzHyMKKhlgzFI2-d5zfrHzd8435n-Tu-5sb14xQhkksMHMbROzC71-yshS7gm_t3zn59_vRz8zW7_v7l22Z9nZlS1jGzypoalrZuTZOKzI1swJpGJaUWjGqrVZlXtUUUythWFKUSBYBtoLUgGijm7P2Jd5yaHq3BIXro9JiEgj9qB6Sf_wy001t30MnppRLJ1zl7e8_g3Z-kP-qegsGugwHdFHSupKhzqYRK0OoENd6F4LF93CPFHWGl9_ohOn0XnT5FlwYvn175OPaQVQJ8OAEweXUg9DoYwsGgJY8mauvofztuAUUdskY</recordid><startdate>20230701</startdate><enddate>20230701</enddate><creator>Dinesh, T.V.</creator><creator>Malgija, Beutline</creator><creator>Ponraj, Mano Ranjana</creator><creator>Muralakar, Pavankumar</creator><creator>Thathapudi, Jesse Joel</creator><creator>Kandasamy, Ruckmani</creator><creator>Alagarmalai, Jeyasankar</creator><creator>Balakrishnan, Anna Benedict</creator><creator>Ramar, Perumal Samy</creator><creator>James, Jannet Vennila</creator><creator>Bhagavathsingh, Jebasingh</creator><general>Elsevier B.V</general><general>Published by Elsevier 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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20230701</creationdate><title>Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach</title><author>Dinesh, T.V. ; Malgija, Beutline ; Ponraj, Mano Ranjana ; Muralakar, Pavankumar ; Thathapudi, Jesse Joel ; Kandasamy, Ruckmani ; Alagarmalai, Jeyasankar ; Balakrishnan, Anna Benedict ; Ramar, Perumal Samy ; James, Jannet Vennila ; Bhagavathsingh, Jebasingh</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c419t-d8dc9a5d9fcbd9f12c1badcb8879dac8f674269dee08cdf034803aadbafda0ba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Antiviral Agents - chemistry</topic><topic>Corona virus</topic><topic>Covalent docking</topic><topic>COVID-19</topic><topic>COVID-19 Drug Treatment</topic><topic>Humans</topic><topic>Main protease</topic><topic>Molecular Docking Simulation</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular dynamics simulations</topic><topic>Molecular modelling</topic><topic>Pyrimidine based remdesivir analogues</topic><topic>Pyrimidines - pharmacology</topic><topic>RNA-dependent DNA polymerase</topic><topic>RNA-Dependent RNA Polymerase - genetics</topic><topic>SARS CoV-2</topic><topic>SARS-CoV-2 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dinesh, T.V.</creatorcontrib><creatorcontrib>Malgija, Beutline</creatorcontrib><creatorcontrib>Ponraj, Mano Ranjana</creatorcontrib><creatorcontrib>Muralakar, Pavankumar</creatorcontrib><creatorcontrib>Thathapudi, Jesse Joel</creatorcontrib><creatorcontrib>Kandasamy, Ruckmani</creatorcontrib><creatorcontrib>Alagarmalai, Jeyasankar</creatorcontrib><creatorcontrib>Balakrishnan, Anna Benedict</creatorcontrib><creatorcontrib>Ramar, Perumal Samy</creatorcontrib><creatorcontrib>James, Jannet Vennila</creatorcontrib><creatorcontrib>Bhagavathsingh, Jebasingh</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of biological macromolecules</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dinesh, T.V.</au><au>Malgija, Beutline</au><au>Ponraj, Mano Ranjana</au><au>Muralakar, Pavankumar</au><au>Thathapudi, Jesse Joel</au><au>Kandasamy, Ruckmani</au><au>Alagarmalai, Jeyasankar</au><au>Balakrishnan, Anna Benedict</au><au>Ramar, Perumal Samy</au><au>James, Jannet Vennila</au><au>Bhagavathsingh, Jebasingh</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach</atitle><jtitle>International journal of biological macromolecules</jtitle><addtitle>Int J Biol Macromol</addtitle><date>2023-07-01</date><risdate>2023</risdate><volume>242</volume><issue>Pt 1</issue><spage>124443</spage><pages>124443-</pages><artnum>124443</artnum><issn>0141-8130</issn><issn>1879-0003</issn><eissn>1879-0003</eissn><abstract>As the world undergone unpreceded time of tragedy with the corona virus, many researchers have raised to showcase their scientific contributions in terms of novel configured anti-viral drugs until now. 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| identifier | ISSN: 0141-8130 |
| ispartof | International journal of biological macromolecules, 2023-07, Vol.242 (Pt 1), p.124443, Article 124443 |
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| language | eng |
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| source | MEDLINE; ScienceDirect Journals (5 years ago - present) |
| subjects | Antiviral Agents - chemistry Corona virus Covalent docking COVID-19 COVID-19 Drug Treatment Humans Main protease Molecular Docking Simulation Molecular Dynamics Simulation Molecular dynamics simulations Molecular modelling Pyrimidine based remdesivir analogues Pyrimidines - pharmacology RNA-dependent DNA polymerase RNA-Dependent RNA Polymerase - genetics SARS CoV-2 SARS-CoV-2 - metabolism |
| title | Design of novel pyrimidine based remdesivir analogues with dual target specificity for SARS CoV-2: A computational approach |
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