title: In Silico Approaches to the Design of NS5A Inhibitors.
abstract: In recent years, nonstructural protein 5A (NS5A) has rapidly emerged as a promising therapeutic target for Hepatitis C (HCV) virus therapy. It is involved in both viral RNA replication and virus assembly and NS5A plays a critical role in the regulation of HCV life cycle. NS5A replication complex inhibitors (NS5A RCIs) have demonstrated strong antiviral activity in vitro and in vivo. However, wild-type resistance mutations and a wide range of genotypes significantly reduce their clinical efficacy. The exact mechanism of NS5A action still remains elusive, therefore several in silico models have been constructed to gain insight into the drug binding and subsequent structural optimization to overcome resistance. This paper provides a comprehensive overview of the computational studies towards NS5A mechanism of action and the design of novel small-molecule inhibitors.
authors.affiliation: Moscow Institute of Physics and Technology (State University), 9 Institutskiy lane, Dolgoprudny city, Moscow Region, 141700, Russia. yai@chemdiv.com.
authors.forename: Yan A
authors.initials: YA
authors.lastname: Ivanenkov
authors.forename: Mark S
authors.initials: MS
authors.lastname: Veselov
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Aladinskiy
authors.forename: Artem G
authors.initials: AG
authors.lastname: Shakhbazyan
authors.forename: Sofya M
authors.initials: SM
authors.lastname: Yartseva
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Majouga
authors.forename: Anastasia V
authors.initials: AV
authors.lastname: Aladinskaya
authors.forename: Anton S
authors.initials: AS
authors.lastname: Vantskul
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Leonov
authors.forename: Alexandre V
authors.initials: AV
authors.lastname: Ivachtchenko
authors.forename: Victor E
authors.initials: VE
authors.lastname: Koteliansky
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase