5HMZ

Dengue serotype 3 RNA-dependent RNA polymerase bound to compound 23

Summary for 5HMZ

• Entry DOI: 10.2210/pdb5hmz/pdb
• Related: 5HMW 5HMX 5HMY 5HN0
• Descriptor: RNA-directed RNA polymerase NS5, ZINC ION, 5-(5-(3-hydroxyprop-1-yn-1-yl)thiophen-2-yl)-4-methoxy-2-methyl-N-(methylsulfonyl)benzamide, ... (4 entities in total)
• Functional Keywords: inhibitor complex polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Dengue virus 3
• Total number of polymer chains: 1
• Total formula weight: 74135.14

Authors

Noble, C.G. (deposition date: 2016-01-17, release date: 2016-03-30, Last modification date: 2023-11-08)

Primary citation

Yokokawa, F.,Nilar, S.,Noble, C.G.,Lim, S.P.,Rao, R.,Tania, S.,Wang, G.,Lee, G.,Hunziker, J.,Karuna, R.,Manjunatha, U.,Shi, P.Y.,Smith, P.W.
Discovery of Potent Non-Nucleoside Inhibitors of Dengue Viral RNA-Dependent RNA Polymerase from a Fragment Hit Using Structure-Based Drug Design
J.Med.Chem., 59:3935-3952, 2016

PubMed Abstract: 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.

PubMed: 26984786
DOI: 10.1021/acs.jmedchem.6b00143

Experimental method

X-RAY DIFFRACTION (1.99 Å)