3H2L

Crystal structure of HCV NS5B polymerase in complex with a novel bicyclic dihydro-pyridinone inhibitor

Summary for 3H2L

• Entry DOI: 10.2210/pdb3h2l/pdb
• Descriptor: NS5B polymerase, N-{3-[(4aR,7aS)-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[b]pyridin-3-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide (3 entities in total)
• Functional Keywords: protein-ligand complex, hepatitis c, rna replication, rna-binding, rna-directed rna polymerase, transferase, acetylation, apoptosis, atp-binding
• Biological source: Hepatitis C virus (isolate BK) (virus)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• Total number of polymer chains: 2
• Total formula weight: 129760.64

Authors

Han, Q.,Showalter, R.E.,Zhou, Q.,Kissinger, C.R. (deposition date: 2009-04-14, release date: 2009-12-08, Last modification date: 2024-04-03)

Primary citation

Ruebsam, F.,Murphy, D.E.,Tran, C.V.,Li, L.S.,Zhao, J.,Dragovich, P.S.,McGuire, H.M.,Xiang, A.X.,Sun, Z.,Ayida, B.K.,Blazel, J.K.,Kim, S.H.,Zhou, Y.,Han, Q.,Kissinger, C.R.,Webber, S.E.,Showalter, R.E.,Shah, A.M.,Tsan, M.,Patel, R.A.,Thompson, P.A.,Lebrun, L.A.,Hou, H.J.,Kamran, R.,Sergeeva, M.V.,Bartkowski, D.M.,Nolan, T.G.,Norris, D.A.,Khandurina, J.,Brooks, J.,Okamoto, E.,Kirkovsky, L.
Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.
Bioorg.Med.Chem.Lett., 19:6404-6412, 2009

PubMed Abstract: A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.

PubMed: 19818610
DOI: 10.1016/j.bmcl.2009.09.045

Experimental method

X-RAY DIFFRACTION (1.9 Å)