5TWN

CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS NS5B RNA- DEPENDENT RNA POLYMERASE IN COMPLEX WITH 5-[3-(tert-butylcarbamoyl)phenyl]-6-(ethylamino)-2-(4-fluorophenyl)-N-methylfuro[2,3-b]pyridine-3-carboxamide

Summary for 5TWN

• Entry DOI: 10.2210/pdb5twn/pdb
• Related: 5TWM
• Descriptor: NS5B RNA- DEPENDENT RNA POLYMERASE, (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid, SULFATE ION, ... (4 entities in total)
• Functional Keywords: ns5b, polymerase, hcv, fingers, palm, thumb, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus genotype 1b (isolate Con1) (HCV)
• Total number of polymer chains: 2
• Total formula weight: 130825.81

Authors

Sheriff, S. (deposition date: 2016-11-14, release date: 2017-03-15, Last modification date: 2023-10-04)

Primary citation

Eastman, K.J.,Parcella, K.,Yeung, K.S.,Grant-Young, K.A.,Zhu, J.,Wang, T.,Zhang, Z.,Yin, Z.,Beno, B.R.,Sheriff, S.,Kish, K.,Tredup, J.,Jardel, A.G.,Halan, V.,Ghosh, K.,Parker, D.,Mosure, K.,Fang, H.,Wang, Y.K.,Lemm, J.,Zhuo, X.,Hanumegowda, U.,Rigat, K.,Donoso, M.,Tuttle, M.,Zvyaga, T.,Haarhoff, Z.,Meanwell, N.A.,Soars, M.G.,Roberts, S.B.,Kadow, J.F.
The discovery of a pan-genotypic, primer grip inhibitor of HCV NS5B polymerase.
Medchemcomm, 8:796-806, 2017

PubMed Abstract: The development of a series of novel 7-azabenzofurans exhibiting pan-genotype inhibition of HCV NS5B polymerase binding to the primer grip site is presented. Many challenges, including poor oral bioavailability, high clearance, bioactivation, high human serum shift, and metabolic stability were encountered and overcome through SAR studies. This work culminated in the selection of BMS-986139 () as a preclinical candidate.

PubMed: 30108798
DOI: 10.1039/c6md00636a

Experimental method

X-RAY DIFFRACTION (3.04 Å)