5HMX

Dengue serotype 3 RNA-dependent RNA polymerase bound to compound 10

5HMX の概要

• エントリーDOI: 10.2210/pdb5hmx/pdb
• 関連するPDBエントリー: 5HMW 5HMY 5HMZ 5HN0
• 分子名称: RNA-directed RNA polymerase NS5, ZINC ION, 2,2'-(5-(thiophen-2-yl)-1,3-phenylene)diacetic acid, ... (4 entities in total)
• 機能のキーワード: inhibitor complex polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Dengue virus 3
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 74308.30

構造登録者

Noble, C.G. (登録日: 2016-01-17, 公開日: 2016-03-30, 最終更新日: 2023-11-08)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.4 Å)