Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals
Dengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA pol...
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2025
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| _version_ | 1852017103786213376 |
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| author | Manisha Saini (345240) |
| author2 | Jasmin C. Aschenbrenner (20468169) Francesc Xavier Ruiz (20113904) Ashima Chopra (15374213) Anu V. Chandran (3614528) Peter G. Marples (22169457) Blake H. Balcomb (22169460) Daren Fearon (13990039) Frank von Delft (7879808) Eddy Arnold (380419) |
| author2_role | author author author author author author author author author |
| author_facet | Manisha Saini (345240) Jasmin C. Aschenbrenner (20468169) Francesc Xavier Ruiz (20113904) Ashima Chopra (15374213) Anu V. Chandran (3614528) Peter G. Marples (22169457) Blake H. Balcomb (22169460) Daren Fearon (13990039) Frank von Delft (7879808) Eddy Arnold (380419) |
| author_role | author |
| dc.creator.none.fl_str_mv | Manisha Saini (345240) Jasmin C. Aschenbrenner (20468169) Francesc Xavier Ruiz (20113904) Ashima Chopra (15374213) Anu V. Chandran (3614528) Peter G. Marples (22169457) Blake H. Balcomb (22169460) Daren Fearon (13990039) Frank von Delft (7879808) Eddy Arnold (380419) |
| dc.date.none.fl_str_mv | 2025-09-02T14:51:34Z |
| dc.identifier.none.fl_str_mv | 10.1021/acs.jmedchem.5c01014.s003 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/dataset/Crystallographic_Fragment_Screening_of_the_Dengue_Virus_Polymerase_Reveals_Multiple_Binding_Sites_for_the_Development_of_Non-nucleoside_Antiflavivirals/30032310 |
| dc.rights.none.fl_str_mv | CC BY-NC 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biophysics Biochemistry Medicine Genetics Molecular Biology Pharmacology Cancer Mental Health Infectious Diseases Virology Computational Biology offer valuable insights nonstructural protein 5 involved 1108 fragments effective therapeutics available binding hot spot thumb site ii novel binding site dependent rna polymerase denv serotype 2 antiviral drug development crystallographic fragment screening active site rna tunnel nucleoside inhibitors n pocket future structure flaviviral rdrps |
| dc.title.none.fl_str_mv | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| dc.type.none.fl_str_mv | Dataset info:eu-repo/semantics/publishedVersion dataset |
| description | Dengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the nonstructural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hot spot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps. |
| eu_rights_str_mv | openAccess |
| id | Manara_d4db3788f1aba4e4e7052c0d882bd747 |
| identifier_str_mv | 10.1021/acs.jmedchem.5c01014.s003 |
| network_acronym_str | Manara |
| network_name_str | ManaraRepo |
| oai_identifier_str | oai:figshare.com:article/30032310 |
| publishDate | 2025 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY-NC 4.0 |
| spelling | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside AntiflaviviralsManisha Saini (345240)Jasmin C. Aschenbrenner (20468169)Francesc Xavier Ruiz (20113904)Ashima Chopra (15374213)Anu V. Chandran (3614528)Peter G. Marples (22169457)Blake H. Balcomb (22169460)Daren Fearon (13990039)Frank von Delft (7879808)Eddy Arnold (380419)BiophysicsBiochemistryMedicineGeneticsMolecular BiologyPharmacologyCancerMental HealthInfectious DiseasesVirologyComputational Biologyoffer valuable insightsnonstructural protein 5involved 1108 fragmentseffective therapeutics availablebinding hot spotthumb site iinovel binding sitedependent rna polymerasedenv serotype 2antiviral drug developmentcrystallographic fragment screeningactive siterna tunnelnucleoside inhibitorsn pocketfuture structureflaviviral rdrpsDengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the nonstructural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hot spot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps.2025-09-02T14:51:34ZDatasetinfo:eu-repo/semantics/publishedVersiondataset10.1021/acs.jmedchem.5c01014.s003https://figshare.com/articles/dataset/Crystallographic_Fragment_Screening_of_the_Dengue_Virus_Polymerase_Reveals_Multiple_Binding_Sites_for_the_Development_of_Non-nucleoside_Antiflavivirals/30032310CC BY-NC 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/300323102025-09-02T14:51:34Z |
| spellingShingle | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals Manisha Saini (345240) Biophysics Biochemistry Medicine Genetics Molecular Biology Pharmacology Cancer Mental Health Infectious Diseases Virology Computational Biology offer valuable insights nonstructural protein 5 involved 1108 fragments effective therapeutics available binding hot spot thumb site ii novel binding site dependent rna polymerase denv serotype 2 antiviral drug development crystallographic fragment screening active site rna tunnel nucleoside inhibitors n pocket future structure flaviviral rdrps |
| status_str | publishedVersion |
| title | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| title_full | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| title_fullStr | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| title_full_unstemmed | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| title_short | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| title_sort | Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals |
| topic | Biophysics Biochemistry Medicine Genetics Molecular Biology Pharmacology Cancer Mental Health Infectious Diseases Virology Computational Biology offer valuable insights nonstructural protein 5 involved 1108 fragments effective therapeutics available binding hot spot thumb site ii novel binding site dependent rna polymerase denv serotype 2 antiviral drug development crystallographic fragment screening active site rna tunnel nucleoside inhibitors n pocket future structure flaviviral rdrps |