Crystallographic Fragment Screening of the Dengue Virus Polymerase Reveals Multiple Binding Sites for the Development of Non-nucleoside Antiflavivirals.

Saini M., Aschenbrenner JC., Ruiz FX., Chopra A., Chandran AV., Marples PG., Balcomb BH., Fearon D., von Delft F., Arnold E.

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.

DOI

10.1021/acs.jmedchem.5c01014

Type

Journal article

Publication Date

2025-09-01T00:00:00+00:00

Volume

68

Pages

18356 - 18369

Total pages

13

Addresses

Center for Advanced Biotechnology and Medicine, Rutgers, the State University of New Jersey, Piscataway, New Jersey 08854, United States.

Keywords

Humans, Dengue Virus, Viral Nonstructural Proteins, Antiviral Agents, Crystallography, X-Ray, Binding Sites, Models, Molecular, RNA-Dependent RNA Polymerase

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