Identification of RdRp-NiRAN/JAK1 Dual-Target Drugs for COVID-19 Treatment
Inhibition of virus replication and inflammatory response is important for the treatment of severe COVID-19 patients. RNA-dependent RNA polymerase (RdRp) is indispensable for SARS-CoV-2 replication, and Janus kinase (JAK) 1 inhibitors exert immunosuppressive effects. RdRp/JAK1 dual-target drugs are...
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| Veröffentlicht in: | The journal of physical chemistry. B 2024-12, Vol.128 (49), p.12066-12077 |
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| container_title | The journal of physical chemistry. B |
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| creator | Zhao, Huixuan Chang, Xiaoyu Sun, Lei Li, Ertong Zhang, Depeng Qi, Wentao Chai, Jijie Hu, Xueping Deng, Weiqiao |
| description | Inhibition of virus replication and inflammatory response is important for the treatment of severe COVID-19 patients. RNA-dependent RNA polymerase (RdRp) is indispensable for SARS-CoV-2 replication, and Janus kinase (JAK) 1 inhibitors exert immunosuppressive effects. RdRp/JAK1 dual-target drugs are expected to ameliorate the severity of the COVID-19 disease. The N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain of RdRp is a pseudokinase, and it has structural similarities with JAK1. Herein, we evaluated the inhibitory effects of triphosphate forms of 31 nucleoside drugs in the DrugBank database on the NiRAN domain and JAK1 through a combination of theoretical and experimental methods. By analyzing the three properties of 31 nucleoside drugs (total hydrophobic surface area, number of hydrophobic atoms, and molecular weight), these drugs met the application rule of our developed molecular docking with conformer-dependent charges (MDCC). Based on the MDCC method combined with molecular dynamics simulations, Azvudine and Citicoline among these 31 drugs showed stronger predicted binding affinities with the NiRAN domain as well as JAK1 compared to the reference drug Remdesivir. Further experimental verification, including a thermal shift assay and homogeneous time-resolved fluorescence assay, demonstrated that Azvudine was an RdRp-NiRAN/JAK1 dual-target drug. This work provided a previously unexplored mechanism of Azvudine for COVID-19 treatment and proposed a design concept for RdRp-NiRAN/JAK1 dual-target nucleoside drugs. |
| doi_str_mv | 10.1021/acs.jpcb.4c06123 |
| format | Article |
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RNA-dependent RNA polymerase (RdRp) is indispensable for SARS-CoV-2 replication, and Janus kinase (JAK) 1 inhibitors exert immunosuppressive effects. RdRp/JAK1 dual-target drugs are expected to ameliorate the severity of the COVID-19 disease. The N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain of RdRp is a pseudokinase, and it has structural similarities with JAK1. Herein, we evaluated the inhibitory effects of triphosphate forms of 31 nucleoside drugs in the DrugBank database on the NiRAN domain and JAK1 through a combination of theoretical and experimental methods. By analyzing the three properties of 31 nucleoside drugs (total hydrophobic surface area, number of hydrophobic atoms, and molecular weight), these drugs met the application rule of our developed molecular docking with conformer-dependent charges (MDCC). Based on the MDCC method combined with molecular dynamics simulations, Azvudine and Citicoline among these 31 drugs showed stronger predicted binding affinities with the NiRAN domain as well as JAK1 compared to the reference drug Remdesivir. Further experimental verification, including a thermal shift assay and homogeneous time-resolved fluorescence assay, demonstrated that Azvudine was an RdRp-NiRAN/JAK1 dual-target drug. This work provided a previously unexplored mechanism of Azvudine for COVID-19 treatment and proposed a design concept for RdRp-NiRAN/JAK1 dual-target nucleoside drugs.</description><identifier>ISSN: 1520-6106</identifier><identifier>ISSN: 1520-5207</identifier><identifier>EISSN: 1520-5207</identifier><identifier>DOI: 10.1021/acs.jpcb.4c06123</identifier><identifier>PMID: 39625254</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; B: Biophysical and Biochemical Systems and Processes ; COVID-19 Drug Treatment ; COVID-19 infection ; domain ; drugs ; fluorescence ; Humans ; hydrophobicity ; immunosuppression ; inflammation ; Janus Kinase 1 - antagonists & inhibitors ; Janus Kinase 1 - chemistry ; Janus Kinase 1 - metabolism ; Molecular Docking Simulation ; molecular dynamics ; Molecular Dynamics Simulation ; molecular weight ; non-specific protein-tyrosine kinase ; nucleosides ; RNA-Dependent RNA Polymerase - antagonists & inhibitors ; RNA-Dependent RNA Polymerase - chemistry ; RNA-Dependent RNA Polymerase - metabolism ; RNA-directed RNA polymerase ; SARS-CoV-2 - drug effects ; SARS-CoV-2 - enzymology ; Severe acute respiratory syndrome coronavirus 2 ; surface area ; virus replication</subject><ispartof>The journal of physical chemistry. 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B</title><addtitle>J. Phys. Chem. B</addtitle><description>Inhibition of virus replication and inflammatory response is important for the treatment of severe COVID-19 patients. RNA-dependent RNA polymerase (RdRp) is indispensable for SARS-CoV-2 replication, and Janus kinase (JAK) 1 inhibitors exert immunosuppressive effects. RdRp/JAK1 dual-target drugs are expected to ameliorate the severity of the COVID-19 disease. The N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain of RdRp is a pseudokinase, and it has structural similarities with JAK1. Herein, we evaluated the inhibitory effects of triphosphate forms of 31 nucleoside drugs in the DrugBank database on the NiRAN domain and JAK1 through a combination of theoretical and experimental methods. By analyzing the three properties of 31 nucleoside drugs (total hydrophobic surface area, number of hydrophobic atoms, and molecular weight), these drugs met the application rule of our developed molecular docking with conformer-dependent charges (MDCC). Based on the MDCC method combined with molecular dynamics simulations, Azvudine and Citicoline among these 31 drugs showed stronger predicted binding affinities with the NiRAN domain as well as JAK1 compared to the reference drug Remdesivir. Further experimental verification, including a thermal shift assay and homogeneous time-resolved fluorescence assay, demonstrated that Azvudine was an RdRp-NiRAN/JAK1 dual-target drug. 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B</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Huixuan</au><au>Chang, Xiaoyu</au><au>Sun, Lei</au><au>Li, Ertong</au><au>Zhang, Depeng</au><au>Qi, Wentao</au><au>Chai, Jijie</au><au>Hu, Xueping</au><au>Deng, Weiqiao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of RdRp-NiRAN/JAK1 Dual-Target Drugs for COVID-19 Treatment</atitle><jtitle>The journal of physical chemistry. B</jtitle><addtitle>J. Phys. Chem. B</addtitle><date>2024-12-12</date><risdate>2024</risdate><volume>128</volume><issue>49</issue><spage>12066</spage><epage>12077</epage><pages>12066-12077</pages><issn>1520-6106</issn><issn>1520-5207</issn><eissn>1520-5207</eissn><abstract>Inhibition of virus replication and inflammatory response is important for the treatment of severe COVID-19 patients. RNA-dependent RNA polymerase (RdRp) is indispensable for SARS-CoV-2 replication, and Janus kinase (JAK) 1 inhibitors exert immunosuppressive effects. RdRp/JAK1 dual-target drugs are expected to ameliorate the severity of the COVID-19 disease. The N-terminal nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain of RdRp is a pseudokinase, and it has structural similarities with JAK1. Herein, we evaluated the inhibitory effects of triphosphate forms of 31 nucleoside drugs in the DrugBank database on the NiRAN domain and JAK1 through a combination of theoretical and experimental methods. By analyzing the three properties of 31 nucleoside drugs (total hydrophobic surface area, number of hydrophobic atoms, and molecular weight), these drugs met the application rule of our developed molecular docking with conformer-dependent charges (MDCC). Based on the MDCC method combined with molecular dynamics simulations, Azvudine and Citicoline among these 31 drugs showed stronger predicted binding affinities with the NiRAN domain as well as JAK1 compared to the reference drug Remdesivir. Further experimental verification, including a thermal shift assay and homogeneous time-resolved fluorescence assay, demonstrated that Azvudine was an RdRp-NiRAN/JAK1 dual-target drug. This work provided a previously unexplored mechanism of Azvudine for COVID-19 treatment and proposed a design concept for RdRp-NiRAN/JAK1 dual-target nucleoside drugs.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>39625254</pmid><doi>10.1021/acs.jpcb.4c06123</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-3671-5951</orcidid><orcidid>https://orcid.org/0000-0002-3014-6719</orcidid><orcidid>https://orcid.org/0000-0001-9960-205X</orcidid></addata></record> |
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| subjects | Antiviral Agents - chemistry Antiviral Agents - pharmacology B: Biophysical and Biochemical Systems and Processes COVID-19 Drug Treatment COVID-19 infection domain drugs fluorescence Humans hydrophobicity immunosuppression inflammation Janus Kinase 1 - antagonists & inhibitors Janus Kinase 1 - chemistry Janus Kinase 1 - metabolism Molecular Docking Simulation molecular dynamics Molecular Dynamics Simulation molecular weight non-specific protein-tyrosine kinase nucleosides RNA-Dependent RNA Polymerase - antagonists & inhibitors RNA-Dependent RNA Polymerase - chemistry RNA-Dependent RNA Polymerase - metabolism RNA-directed RNA polymerase SARS-CoV-2 - drug effects SARS-CoV-2 - enzymology Severe acute respiratory syndrome coronavirus 2 surface area virus replication |
| title | Identification of RdRp-NiRAN/JAK1 Dual-Target Drugs for COVID-19 Treatment |
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