In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin
Dengue virus infection is a global health problem for which there have been challenges to obtaining a cure. Current vaccines and anti-viral drugs can only be narrowly applied in ongoing clinical trials. We employed computational methods based on structure-function relationships between human host ki...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Biology |
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| Online Access: | https://www.mdpi.com/2079-7737/10/10/1067 |
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| author | Lamya Alomair Fahad Almsned Aman Ullah Mohsin S. Jafri |
| author_facet | Lamya Alomair Fahad Almsned Aman Ullah Mohsin S. Jafri |
| author_sort | Lamya Alomair |
| collection | DOAJ |
| description | Dengue virus infection is a global health problem for which there have been challenges to obtaining a cure. Current vaccines and anti-viral drugs can only be narrowly applied in ongoing clinical trials. We employed computational methods based on structure-function relationships between human host kinases and viral nonstructural protein 3 (NS3) to understand viral replication inhibitors’ therapeutic effect. Phosphorylation at each of the two most evolutionarily conserved sites of NS3, serine 137 and threonine 189, compared to the unphosphorylated state were studied with molecular dynamics and docking simulations. The simulations suggested that phosphorylation at serine 137 caused a more remarkable structural change than phosphorylation at threonine 189, specifically located at amino acid residues 49–95. Docking studies supported the idea that phosphorylation at serine 137 increased the binding affinity between NS3 and nonstructural Protein 5 (NS5), whereas phosphorylation at threonine 189 decreased it. The interaction between NS3 and NS5 is essential for viral replication. Docking studies with the antiviral plant flavonoid Quercetin with NS3 indicated that Quercetin physically occluded the serine 137 phosphorylation site. Taken together, these findings suggested a specific site and mechanism by which Quercetin inhibits dengue and possible other flaviviruses. |
| first_indexed | 2024-03-10T06:43:24Z |
| format | Article |
| id | doaj.art-639ebb00e8f84849a96753a7b5389523 |
| institution | Directory Open Access Journal |
| issn | 2079-7737 |
| language | English |
| last_indexed | 2024-03-10T06:43:24Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biology |
| spelling | doaj.art-639ebb00e8f84849a96753a7b53895232023-11-22T17:29:18ZengMDPI AGBiology2079-77372021-10-011010106710.3390/biology10101067In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of QuercetinLamya Alomair0Fahad Almsned1Aman Ullah2Mohsin S. Jafri3Department of Biostatistics and Bioinformatics–Bioinformatics Section, King Abdullah International Medical Research Center, Riyadh 11481, Saudi ArabiaThe School of Systems Biology and the Krasnow Institute for Advanced Study, George Mason University, Fairfax, Manassas, VA 22030, USAThe School of Systems Biology and the Krasnow Institute for Advanced Study, George Mason University, Fairfax, Manassas, VA 22030, USAThe School of Systems Biology and the Krasnow Institute for Advanced Study, George Mason University, Fairfax, Manassas, VA 22030, USADengue virus infection is a global health problem for which there have been challenges to obtaining a cure. Current vaccines and anti-viral drugs can only be narrowly applied in ongoing clinical trials. We employed computational methods based on structure-function relationships between human host kinases and viral nonstructural protein 3 (NS3) to understand viral replication inhibitors’ therapeutic effect. Phosphorylation at each of the two most evolutionarily conserved sites of NS3, serine 137 and threonine 189, compared to the unphosphorylated state were studied with molecular dynamics and docking simulations. The simulations suggested that phosphorylation at serine 137 caused a more remarkable structural change than phosphorylation at threonine 189, specifically located at amino acid residues 49–95. Docking studies supported the idea that phosphorylation at serine 137 increased the binding affinity between NS3 and nonstructural Protein 5 (NS5), whereas phosphorylation at threonine 189 decreased it. The interaction between NS3 and NS5 is essential for viral replication. Docking studies with the antiviral plant flavonoid Quercetin with NS3 indicated that Quercetin physically occluded the serine 137 phosphorylation site. Taken together, these findings suggested a specific site and mechanism by which Quercetin inhibits dengue and possible other flaviviruses.https://www.mdpi.com/2079-7737/10/10/1067dengueNS3phosphorylationquercetin |
| spellingShingle | Lamya Alomair Fahad Almsned Aman Ullah Mohsin S. Jafri In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin Biology dengue NS3 phosphorylation quercetin |
| title | In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin |
| title_full | In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin |
| title_fullStr | In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin |
| title_full_unstemmed | In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin |
| title_short | In Silico Prediction of the Phosphorylation of NS3 as an Essential Mechanism for Dengue Virus Replication and the Antiviral Activity of Quercetin |
| title_sort | in silico prediction of the phosphorylation of ns3 as an essential mechanism for dengue virus replication and the antiviral activity of quercetin |
| topic | dengue NS3 phosphorylation quercetin |
| url | https://www.mdpi.com/2079-7737/10/10/1067 |
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