title: A new method for induced fit docking (GENIUS) and its application to virtual screening of novel HCV NS3-4A protease inhibitors.
abstract: Hepatitis C virus (HCV) is an etiologic agent of chronic liver disease, and approximately 170 million people worldwide are infected with the virus. HCV NS3-4A serine protease is essential for the replication of this virus, and thus has been investigated as an attractive target for anti-HCV drugs. In this study, we developed our new induced-fit docking program (genius), and applied it to the discovery of a new class of NS3-4A protease inhibitors (IC(50)=1-10 μM including high selectivity index). The new inhibitors thus identified were modified, based on the docking models, and revealed preliminary structure-activity relationships. Moreover, the genius in silico screening performance was validated by using an enrichment factor. We believe our designed scaffold could contribute to the improvement of HCV chemotherapy.
authors: RIKEN Systems and Structural Biology Center, Tsurumi, Yokohama, Japan.
authors: Daisuke
authors: D
authors: Takaya
authors: Atsuya
authors: A
authors: Yamashita
authors: Kazue
authors: K
authors: Kamijo
authors: Junko
authors: J
authors: Gomi
authors: Masahiko
authors: M
authors: Ito
authors: Shinya
authors: S
authors: Maekawa
authors: Nobuyuki
authors: N
authors: Enomoto
authors: Naoya
authors: N
authors: Sakamoto
authors: Yoshiaki
authors: Y
authors: Watanabe
authors: Ryoichi
authors: R
authors: Arai
authors: Hideaki
authors: H
authors: Umeyama
authors: Teruki
authors: T
authors: Honma
authors: Takehisa
authors: T
authors: Matsumoto
authors: Shigeyuki
authors: S
authors: Yokoyama
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D015842:Serine Proteinase Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases