5HMW: Dengue Serotype 3 Rna-dependent Rna Polymerase Bound To Compound 5

The discovery and optimization of non-nucleoside dengue viral RNA-dependent-RNA polymerase (RdRp) inhibitors are described. An X-ray-based fragment screen of Novartis' fragment collection resulted in the identification of a biphenyl acetic acid fragment 3, which bound in the palm subdomain of RdRp. Subsequent optimization of the fragment hit 3, relying on structure-based design, resulted in a >1000-fold improvement in potency in vitro and acquired antidengue activity against all four serotypes with low micromolar EC50 in cell-based assays. The lead candidate 27 interacts with a novel binding pocket in the palm subdomain of the RdRp and exerts a promising activity against all clinically relevant dengue serotypes.
PDB ID: 5HMWDownload
MMDB ID: 137972
PDB Deposition Date: 2016/1/17
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2.15  Å
Source Organism:
Similar Structures:
Biological Unit for 5HMW: monomeric; determined by author
Molecular Components in 5HMW
Label Count Molecule
Protein (1 molecule)
RNA-directed RNA Polymerase NS5
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB