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.

@article{Prongay2007DiscoveryOT,
  title={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.},
  author={Andrew J. Prongay and Zhuyan Guo and Nanhua Yao and John S Pichardo and Thierry O. Fischmann and Corey Strickland and Joseph Myers and Patricia C. Weber and Brian M. Beyer and Richard N Ingram and Zhi Hong and Winifred W. Prosise and L. S. Ramanathan and Shahriar S. Taremi and Taisa Yarosh-Tomaine and Rumin Zhang and Mary M Senior and Rong-Sheng Yang and Bruce Malcolm and Ashok Arasappan and Frank Bennett and St{\'e}phane L. Bogen and Kevin Chen and Edwin Jao and Yi-Tsung Liu and Raymond G. Lovey and Anil K. Saksena and Srikanth Venkatraman and Viyyoor M. Girijavallabhan and F. George Njoroge and Vincent Madison},
  journal={Journal of medicinal chemistry},
  year={2007},
  volume={50 10},
  pages={2310-8}
}
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… CONTINUE READING

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