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A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening.

ABSTRACT: 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.

SUBMITTER: Noble CG 

PROVIDER: S-EPMC4861426 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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A Conserved Pocket in the Dengue Virus Polymerase Identified through Fragment-based Screening.

Noble Christian G CG   Lim Siew Pheng SP   Arora Rishi R   Yokokawa Fumiaki F   Nilar Shahul S   Seh Cheah Chen CC   Wright S Kirk SK   Benson Timothy E TE   Smith Paul W PW   Shi Pei-Yong PY  

The Journal of biological chemistry 20160212 16

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 compou  ...[more]

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