4OK5

Crystal Structure of Hepatitis C Virus NS3 Helicase Inhibitor Co-complex with Compound 9 [1-(3-ethynylbenzyl)-1H-indol-3-yl]acetic acid]

Summary for 4OK5

• Entry DOI: 10.2210/pdb4ok5/pdb
• Related: 4OJQ 4OK3 4OK6 4OKS
• Descriptor: Serine protease NS3, CALCIUM ION, [1-(3-ethynylbenzyl)-1H-indol-3-yl]acetic acid, ... (4 entities in total)
• Functional Keywords: hepatitis, atpase, ntpase, ns3 helicase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C Virus
• Total number of polymer chains: 2
• Total formula weight: 99930.25

Authors

Padyana, A.K. (deposition date: 2014-01-21, release date: 2014-03-05, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.15 Å)