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4OKS

Crystal Structure of Hepatitis C Virus NS3 Helicase Inhibitor Co-complex with Compound 19 [[6-(3,5-diaminophenyl)-1-(2-methoxy-5-nitrobenzyl)-1H-indol-3-yl]acetic acid]

Summary for 4OKS
Entry DOI10.2210/pdb4oks/pdb
Related4OJQ 4OK3 4OK5 4OK6
DescriptorSerine protease NS3, [6-(3,5-diaminophenyl)-1-(2-methoxy-5-nitrobenzyl)-1H-indol-3-yl]acetic acid, CALCIUM ION, ... (4 entities in total)
Functional Keywordshepatitis, atpase, ntpase, ns3 helicase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
Biological sourceHepatitis C Virus
Total number of polymer chains2
Total formula weight100087.38
Authors
Padyana, A.K. (deposition date: 2014-01-22, release date: 2014-03-05, Last modification date: 2024-02-28)
Primary citationLaplante, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2.25 Å)
Structure validation

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