4OK6

Crystal Structure of Hepatitis C Virus NS3 Helicase Inhibitor Co-complex with Compound 13 [[1-(2-methoxy-5-nitrobenzyl)-1H-indol-3-yl]acetic acid]

4OK6 の概要

• エントリーDOI: 10.2210/pdb4ok6/pdb
• 関連するPDBエントリー: 4OJQ 4OK3 4OK5 4OKS
• 分子名称: Serine protease NS3, CALCIUM ION, [1-(2-methoxy-5-nitrobenzyl)-1H-indol-3-yl]acetic acid, ... (4 entities in total)
• 機能のキーワード: hepatitis, atpase, ntpase, ns3 helicase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Hepatitis C Virus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 99981.25

構造登録者

Padyana, A.K. (登録日: 2014-01-21, 公開日: 2014-03-05, 最終更新日: 2024-02-28)

主引用文献

Laplante, S.R.,Padyana, A.K.,Abeywardane, A.,Bonneau, P.,Cartier, M.,Coulombe, R.,Jakalian, A.,Wildeson-Jones, J.,Li, X.,Liang, S.,McKercher, G.,White, P.,Zhang, Q.,Taylor, S.J.
Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus.
J.Med.Chem., 57:2074-2090, 2014

PubMed Abstract: Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery.

PubMed: 24467709
DOI: 10.1021/jm401432c

実験手法

X-RAY DIFFRACTION (2.4 Å)