2OBQ

Discovery of the HCV NS3/4A Protease Inhibitor SCH503034. Key Steps in Structure-Based Optimization

2OBQ の概要

• エントリーDOI: 10.2210/pdb2obq/pdb
• 関連するPDBエントリー: 1A1R 2A4G 2A4Q 2A4R 2F9V 2FM2
• 分子名称: Hepatitis C virus, ZINC ION, ... (4 entities in total)
• 機能のキーワード: hcv, hepatitis c virus, ns3 protease, viral protein
• 由来する生物種: Hepatitis C virus
• 細胞内の位置: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein. RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : P27958
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 47417.48

構造登録者

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. (登録日: 2006-12-19, 公開日: 2007-07-31, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.5 Å)