2OC7

Structure of Hepatitis C Viral NS3 protease domain complexed with NS4A peptide and ketoamide SCH571696

Summary for 2OC7

• Entry DOI: 10.2210/pdb2oc7/pdb
• Related: 2OBO 2OC0 2OC1
• Descriptor: Hepatitis C Virus, ZINC ION, BETA-MERCAPTOETHANOL, ... (6 entities in total)
• Functional Keywords: hepatitis c virus, hcv, ns3 protease domain, ketoamide inhibitor, viral protein
• Biological source: Hepatitis C virus
• Total number of polymer chains: 4
• Total formula weight: 48026.18

Authors

Prongay, A.J.,Guo, Z.,Yao, N.,Fischmann, T.,Strickland, C.,Myers Jr., J.,Weber, P.C.,Malcolm, B.,Beyer, B.M.,Ingram, R.,Pichardo, J.,Hong, Z.,Prosise, W.W.,Ramanathan, L.,Taremi, S.S.,Yarosh-Tomaine, T.,Zhang, R.,Senior, M.,Yang, R.,Arasappan, A.,Bennett, F.,Bogen, S.F.,Chen, K.,Jao, E.,Liu, Y.,Love, R.G.,Saksena, A.K.,Venkatraman, S.,Girijavallabhan, V.,Njoroge, F.G.,Madison, V. (deposition date: 2006-12-20, release date: 2007-07-31, Last modification date: 2023-08-30)

Primary citation

Prongay, A.J.,Guo, Z.,Yao, N.,Pichardo, J.,Fischmann, T.,Strickland, C.,Myers Jr., J.,Weber, P.C.,Beyer, B.M.,Ingram, R.,Hong, Z.,Prosise, W.W.,Ramanathan, L.,Taremi, S.S.,Yarosh-Tomaine, T.,Zhang, R.,Senior, M.,Yang, R.S.,Malcolm, B.,Arasappan, A.,Bennett, F.,Bogen, S.L.,Chen, K.,Jao, E.,Liu, Y.T.,Lovey, R.G.,Saksena, A.K.,Venkatraman, S.,Girijavallabhan, V.,Njoroge, F.G.,Madison, V.
Discovery of the HCV NS3/4A protease inhibitor (1R,5S)-N-[3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl]-3- [2(S)-[[[(1,1-dimethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexan-2(S)-carboxamide (Sch 503034) II. Key steps in structure-based optimization.
J.Med.Chem., 50:2310-2318, 2007

PubMed Abstract: The structures of both the native holo-HCV NS3/4A protease domain and the protease domain with a serine 139 to alanine (S139A) mutation were solved to high resolution. Subsequently, structures were determined for a series of ketoamide inhibitors in complex with the protease. The changes in the inhibitor potency were correlated with changes in the buried surface area upon binding the inhibitor to the active site. The largest contribution to the binding energy arises from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets [the numbering of the subsites is as defined in Berger, A.; Schechter, I. Philos. Trans. R. Soc. London, Ser. B 1970, 257, 249-264]. This correlation of the changes in potency with increased buried surface area contributed directly to the design of a potent tripeptide inhibitor of the HCV NS3/4A protease that is currently in clinical trials.

PubMed: 17444623
DOI: 10.1021/jm060173k

Experimental method

X-RAY DIFFRACTION (2.7 Å)