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A Conserved Pocket in the Dengue Virus Polymerase Identified Through Fragment-Based Screening

Noble, Christian Guy and Lim, Siew Pheng and Arora, Rishi and Yokokawa, Fumiaki and Nilar, Shahul Hameed and Seh, Cheah Chen and Wright, Kirk and Benson, Timothy and Smith, Paul William and Shi, Pei-Yong (2016) A Conserved Pocket in the Dengue Virus Polymerase Identified Through Fragment-Based Screening. Journal of Biological Chemistry, 291 (16). pp. 8541-8548. ISSN 1083-351X

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 8 identified a single hit that bound in a novel pocket in the protein. This pocket is located in the polymerase palm domain 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.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/27790

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