A conserved pocket in the dengue virus polymerase identified through fragment-based screening

Christian G. Noble, Siew Pheng Lim, Rishi Arora, Fumiaki Yokokawa, Shahul Nilar, Cheah Chen Seh, S. Kirk Wright, Timothy E. Benson, Paul W. Smith, Pei-Yong Shi

Research output: Contribution to journalArticle

24 Scopus citations


We performed a fragment screen on the dengue virus serotype 3 RNA-dependent RNA polymerase using x-ray crystallography. A screen of 1, 400 fragments in pools of eight identified a single hit that bound in a novel pocket in the protein. This pocket is located in the polymerase palm subdomain and conserved across the four serotypes of dengue virus. The compound binds to the polymerase in solution as evidenced by surface plasmon resonance and isothermal titration calorimetry analyses. Related compounds where a phenyl is replaced by a thiophene show higher affinity binding, indicating the potential for rational design. Importantly, inhibition of enzyme activity correlated with the binding affinity, showing that the pocket is functionally important for polymerase activity. This fragment is an excellent starting point for optimization through rational structure based design.

Original languageEnglish (US)
Pages (from-to)8541-8548
Number of pages8
JournalJournal of Biological Chemistry
Issue number16
StatePublished - Apr 15 2016


ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Noble, C. G., Lim, S. P., Arora, R., Yokokawa, F., Nilar, S., Seh, C. C., Wright, S. K., Benson, T. E., Smith, P. W., & Shi, P-Y. (2016). A conserved pocket in the dengue virus polymerase identified through fragment-based screening. Journal of Biological Chemistry, 291(16), 8541-8548. https://doi.org/10.1074/jbc.M115.710731