Open AccessKey steps in the structure‐based optimization of the hepatitis C virus NS3/4A protease inhibitor SCH503034
Author(s) -
Madison Vincent,
Prongay Andrew J.,
Guo Zhuyan,
Yao Nanhua,
Pichardo John,
Fischmann Thierry,
Strickland Corey,
Myers Jr Joseph,
Weber Patricia C.,
Beyer Brian M.,
Ingram Richard,
Hong Zhi,
Prosise Winifred W.,
Ramanathan Lata,
Taremi S. Shane,
YaroshTomaine Taisa,
Zhang Rumin,
Senior Mary,
Yang RongSheng,
Malcolm Bruce,
Arasappan Ashok,
Bennett Frank,
Bogen Stephane L.,
Chen Kevin,
Jao Edwin,
Liu YiTsung,
Lovey Raymond G.,
Saksena Anil K.,
Venkatraman Srikanth,
Girijavallabhan Viyyoor,
Njoroge F. George
Publication year - 2008
Publication title -
journal of synchrotron radiation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.172
H-Index - 99
ISSN - 1600-5775
DOI - 10.1107/s0909049507064229
Subject(s) - ns3 , tripeptide , protease , protease inhibitor (pharmacology) , potency , chemistry , hepatitis c virus , stereochemistry , serine protease , virology , binding site , virus , biochemistry , enzyme , in vitro , biology , peptide , antiretroviral therapy , viral load
The structures of both native and S139A holo‐HCV NS3/4A protease domain 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 contributions to the binding energy arise from the hydrophobic interactions of the P1 and P2 groups as they bind to the S1 and S2 pockets. 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, which is currently in clinical trials.