5E9Q

DENGUE 3 NS5 METHYLTRANSFERASE BOUND TO S-ADENOSYL METHIONINE AND MOLECULE BF174

Summary for 5E9Q

• Entry DOI: 10.2210/pdb5e9q/pdb
• Descriptor: Genome polyprotein, S-ADENOSYLMETHIONINE, 2-({[2-amino-4-(trifluoromethyl)phenyl]carbamoyl}amino)-4-methylbenzoic acid, ... (4 entities in total)
• Functional Keywords: transferase, dengue virus, ns5 methyltransferase, fragment-based drug discovery
• Biological source: Dengue virus 3 (DENV-3)
• Total number of polymer chains: 2
• Total formula weight: 59491.51

Authors

Barral, K.,Bricogne, G.,Sharff, A. (deposition date: 2015-10-15, release date: 2016-10-26, Last modification date: 2024-01-10)

Primary citation

Benmansour, F.,Trist, I.,Coutard, B.,Decroly, E.,Querat, G.,Brancale, A.,Barral, K.
Discovery of novel dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design.
Eur.J.Med.Chem., 125:865-880, 2016

PubMed Abstract: With the aim to help drug discovery against dengue virus (DENV), a fragment-based drug design approach was applied to identify ligands targeting a main component of DENV replication complex: the NS5 AdoMet-dependent mRNA methyltransferase (MTase) domain, playing an essential role in the RNA capping process. Herein, we describe the identification of new inhibitors developed using fragment-based, structure-guided linking and optimization techniques. Thermal-shift assay followed by a fragment-based X-ray crystallographic screening lead to the identification of three fragment hits binding DENV MTase. We considered linking two of them, which bind to proximal sites of the AdoMet binding pocket, in order to improve their potency. X-ray crystallographic structures and computational docking were used to guide the fragment linking, ultimately leading to novel series of non-nucleoside inhibitors of flavivirus MTase, respectively N-phenyl-[(phenylcarbamoyl)amino]benzene-1-sulfonamide and phenyl [(phenylcarbamoyl)amino]benzene-1-sulfonate derivatives, that show a 10-100-fold stronger inhibition of 2'-O-MTase activity compared to the initial fragments.

PubMed: 27750202
DOI: 10.1016/j.ejmech.2016.10.007

Experimental method

X-RAY DIFFRACTION (1.79 Å)