3LOX

HCV NS3-4a protease domain with a ketoamide inhibitor derivative of Boceprevir bound

Summary for 3LOX

• Entry DOI: 10.2210/pdb3lox/pdb
• Related PRD ID: PRD_000843
• Descriptor: HCV NS3 Protease, HCV NS4a(21-39) peptide, ZINC ION, ... (6 entities in total)
• Functional Keywords: ns3 protease domain, serine protease, ketoamide inhibitor, atp-binding, hydrolase, membrane, nucleotide-binding, rna replication, transmembrane, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C virus subtype 1a
• Total number of polymer chains: 4
• Total formula weight: 48025.24

Authors

Prongay, A.J. (deposition date: 2010-02-04, release date: 2011-02-23, Last modification date: 2024-04-03)

Primary citation

Bennett, F.,Huang, Y.,Hendrata, S.,Lovey, R.,Bogen, S.L.,Pan, W.,Guo, Z.,Prongay, A.,Chen, K.X.,Arasappan, A.,Venkatraman, S.,Velazquez, F.,Nair, L.,Sannigrahi, M.,Tong, X.,Pichardo, J.,Cheng, K.C.,Girijavallabhan, V.M.,Saksena, A.K.,Njoroge, F.G.
The introduction of P4 substituted 1-methylcyclohexyl groups into Boceprevir: a change in direction in the search for a second generation HCV NS3 protease inhibitor.
Bioorg.Med.Chem.Lett., 20:2617-2621, 2010

PubMed Abstract: In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.

PubMed: 20303756
DOI: 10.1016/j.bmcl.2010.02.063

Experimental method

X-RAY DIFFRACTION (2.65 Å)