Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.
Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used m...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2021-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0257206 |
| _version_ | 1818436196164960256 |
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| author | R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti |
| author_facet | R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti |
| author_sort | R V Sriram Uday |
| collection | DOAJ |
| description | Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study. |
| first_indexed | 2024-12-14T17:04:56Z |
| format | Article |
| id | doaj.art-5cdadd6cff564a66ac6bfef33c321c75 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-14T17:04:56Z |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5cdadd6cff564a66ac6bfef33c321c752022-12-21T22:53:44ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01169e025720610.1371/journal.pone.0257206Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease.R V Sriram UdayRajdip MisraAnnaram HarikaSandip DoluiAchintya SahaUttam PalV RavichandiranNakul C MaitiDengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.https://doi.org/10.1371/journal.pone.0257206 |
| spellingShingle | R V Sriram Uday Rajdip Misra Annaram Harika Sandip Dolui Achintya Saha Uttam Pal V Ravichandiran Nakul C Maiti Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. PLoS ONE |
| title | Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. |
| title_full | Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. |
| title_fullStr | Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. |
| title_full_unstemmed | Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. |
| title_short | Dabrafenib, idelalisib and nintedanib act as significant allosteric modulator for dengue NS3 protease. |
| title_sort | dabrafenib idelalisib and nintedanib act as significant allosteric modulator for dengue ns3 protease |
| url | https://doi.org/10.1371/journal.pone.0257206 |
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