5QJ0

CRYSTAL STRUCTURE OF THE HEPATITIS C VIRUS GENOTYPE 2A STRAIN JFH1 NS5B RNA-DEPENDENT RNA POLYMERASE IN COMPLEX WITH 6-[ethyl(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-5-(3-{[1-(pyrimidin-2-yl)cyclopropyl]carbamoyl}phenyl)-1-benzofuran-3-carboxamide

Summary for 5QJ0

• Entry DOI: 10.2210/pdb5qj0/pdb
• Group deposition: NS5B 1b (G_1002055)
• Descriptor: RNA-dependent RNA polymerase, 6-[ethyl(methylsulfonyl)amino]-2-(4-fluorophenyl)-N-methyl-5-(3-{[1-(pyrimidin-2-yl)cyclopropyl]carbamoyl}phenyl)-1-benzofuran-3-carboxamide, THIOCYANATE ION, ... (6 entities in total)
• Functional Keywords: rdrp structure (fingers, palm, thumb domains), acetylation, apoptosis, atp-binding, capsid protein, cell membrane, cytoplasm, disulfide bond, endoplasmic reticulum, envelope protein, fusion protein, glycoprotein, helicase, host-virus interaction, hydrolase, interferon antiviral system evasion, lipid droplet, lipoprotein, membrane, metal- binding, mitochondrion, multifunctional enzyme, nucleotide- binding, nucleotidyltransferase, nucleus, oncogene, palmitate, phosphoprotein, protease, ribonucleoprotein, rna replication, rna-binding, rna-directed rna polymerase, secreted, serine protease, sh3-binding, thiol protease, transcription, transcription regulation, transferase, transmembrane, ubl conjugation, viral nucleoprotein, virion, zinc, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepacivirus C
• Total number of polymer chains: 1
• Total formula weight: 65608.29

Authors

Sheriff, S. (deposition date: 2018-08-13, release date: 2018-11-21, Last modification date: 2024-03-06)

Primary citation

Yeung, K.S.,Beno, B.R.,Mosure, K.,Zhu, J.,Grant-Young, K.A.,Parcella, K.,Anjanappa, P.,Bora, R.O.,Selvakumar, K.,Wang, Y.K.,Fang, H.,Krause, R.,Rigat, K.,Liu, M.,Lemm, J.,Sheriff, S.,Witmer, M.,Tredup, J.,Jardel, A.,Kish, K.,Parker, D.,Haskell, R.,Santone, K.,Meanwell, N.A.,Soars, M.G.,Roberts, S.B.,Kadow, J.F.
Structure-Property Basis for Solving Transporter-Mediated Efflux and Pan-Genotypic Inhibition in HCV NS5B Inhibitors.
ACS Med Chem Lett, 9:1217-1222, 2018

PubMed Abstract: In solving the P-gp and BCRP transporter-mediated efflux issue in a series of benzofuran-derived pan-genotypic palm site inhibitors of the hepatitis C virus NS5B replicase, it was found that close attention to physicochemical properties was essential. In these compounds, where both molecular weight (MW >579) and TPSA (>110 Å) were high, attenuation of polar surface area together with weakening of hydrogen bond acceptor strength of the molecule provided a higher intrinsic membrane permeability and more desirable Caco-2 parameters, as demonstrated by trifluoroacetamide and the benchmark -ethylamino analog . In addition, the tendency of these inhibitors to form intramolecular hydrogen bonds potentially contributes favorably to the improved membrane permeability and absorption. The functional group minimization that resolved the efflux problem simultaneously maintained potent inhibitory activity toward a gt-2 HCV replicon due to a switching of the role of substituents in interacting with the Gln414 binding pocket, as observed in gt-2a NS5B/inhibitor complex cocrystal structures, thus increasing the efficiency of the optimization. Noteworthy, a novel intermolecular S=O···C=O type interaction between the ligand sulfonamide oxygen atom and the carbonyl moiety of the side chain of Gln414 was observed. The insights from these structure-property studies and crystallography information provided a direction for optimization in a campaign to identify second generation pan-genotypic NS5B inhibitors.

PubMed: 30613329
DOI: 10.1021/acsmedchemlett.8b00379

Experimental method

X-RAY DIFFRACTION (2.08 Å)