Multiple e-Pharmacophore Modeling, 3D-QSAR, and High-Throughput Virtual Screening of Hepatitis C Virus NS5B Polymerase Inhibitors

2014 ◽  
Vol 54 (2) ◽  
pp. 539-552 ◽  
Author(s):  
Patrisha Joseph Therese ◽  
Dinesh Manvar ◽  
Sridevi Kondepudi ◽  
Madhu Babu Battu ◽  
Dharmarajan Sriram ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virtual Screening ◽  
High Throughput ◽  
3D Qsar ◽  
Pharmacophore Modeling ◽  
Polymerase Inhibitors ◽  
Ns5b Polymerase ◽  
High Throughput Virtual Screening

3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

2016 ◽  
Vol 1117 ◽  
pp. 227-239 ◽  
Author(s):  
Wenlian Li ◽  
Hongzong Si ◽  
Yang Li ◽  
Cuizhu Ge ◽  
Fucheng Song ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
3D Qsar ◽  
Docking Studies ◽  
Molecular Docking Studies ◽  
Ns5b Polymerase

scholarly journals Selection of Replicon Variants Resistant to ACH-806, a Novel Hepatitis C Virus Inhibitor with No Cross-Resistance to NS3 Protease and NS5B Polymerase Inhibitors

2008 ◽  
Vol 52 (6) ◽  
pp. 2043-2052 ◽  
Author(s):  
Wengang Yang ◽  
Yongsen Zhao ◽  
Joanne Fabrycki ◽  
Xiaohong Hou ◽  
Xingtie Nie ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Amino Acid ◽  
Protease Inhibitors ◽  
Cross Resistance ◽  
Polymerase Inhibitors ◽  
Ns3 Protease Inhibitors ◽  
Ns3 Protease ◽  
Ns5b Polymerase ◽  
Selection Of

ABSTRACT We have discovered a novel class of compounds active against hepatitis C virus (HCV), using a surrogate cellular system, HCV replicon cells. The leading compound in the series, ACH-806 (GS-9132), is a potent and specific inhibitor of HCV. The selection of resistance replicon variants against ACH-806 was performed to map the mutations conferring resistance to ACH-806 and to determine cross-resistance profiles with other classes of HCV inhibitors. Several clones emerged after the addition of ACH-806 to HCV replicon cells at frequencies and durations similar to that observed with NS3 protease inhibitors and NS5B polymerase inhibitors. Phenotypic analyses of these clones revealed that they are resistant to ACH-806 but remain sensitive to other classes of HCV inhibitors. Moreover, no significant change in the susceptibility to ACH-806 was found when the replicon cellular clones resistant to NS3 protease inhibitors and NS5B polymerase inhibitors were examined. Sequencing of the entire coding region of ACH-806-resistant replicon variants yielded several consensus mutations. Reverse genetics identified two single mutations in NS3, a cysteine-to-serine mutation at amino acid 16 and an alanine-to-valine mutation at amino acid 39, that are responsible for the resistance of the replicon variants to ACH-806. Both mutations are located at the N terminus of NS3 where extensive interactions with the central hydrophobic region of NS4A exist. These data provide evidence that ACH-806 inhibits HCV replication by a novel mechanism.

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