Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

“…In their recent publication, Talele et al [40] presented a virtual screening workflow to identify and further design novel HCV NS5B polymerase inhibitors. The proposed methodology employs structure-based virtual screening, synthesis and structure -activity relationship (SAR) optimization approach.…”

Section: In Silico Strategies -Identifying Hcv Inhibi-torsmentioning

confidence: 99%

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors

Melagraki¹,

Afantitis

2011

CMC

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Virtual Screening (VS) has experienced increased attention into the recent years due to the large datasets made available, the development of advanced VS techniques and the encouraging fact that VS has contributed to the discovery of several compounds that have either reached the market or entered clinical trials. Hepatitis C Virus (HCV) nonstructural protein 5B (NS5B) has become an attractive target for the development of antiviral drugs and many small molecules have been explored as possible HCV NS5B inhibitors. In parallel with experimental practices, VS can serve as a valuable tool in the identification of novel effective inhibitors. Different techniques and workflows have been reported in literature with the goal to prioritize possible potent hits. In this context, different virtual screening strategies have been deployed for the identification of novel Hepatitis C Virus (HCV) inhibitors. This work reviews recent applications of virtual screening in an effort to identify novel potent HCV inhibitors.

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“…Compounds bearing the rhodanine scaffold have been previously reported as HCV NS5B inhibitors, by us 16 and others. 17 Recently, the rhodanine scaffold has been a topic of debate in regards to its promiscuous nature.…”

Section: Introductionmentioning

confidence: 94%

Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase

Patel

Krishnan

Khadtare

et al. 2013

Bioorganic & Medicinal Chemistry

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Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development. Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC50 = 7.7 µM) and 2 (IC50 = 10.6 µM) as represented by hybrid compound 27 (IC50 = 6.7 µM). We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC50 of 2.6 µM. To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the D-isomers 41 (IC50 = 19.3 µM) and 45 (IC50 = 5.4 µM) as enantiomers of the L-isomers 27 and 34, respectively. The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.

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Structure-based virtual screening, synthesis and SAR of novel inhibitors of hepatitis C virus NS5B polymerase

Cited by 73 publications

References 52 publications

New thiopyrano[2,3-d][1,3]thiazole derivatives as potential antiviral agents

New thiopyrano[2,3-d][1,3]thiazole derivatives as potential antiviral agents

Ligand and Structure Based Virtual Screening Strategies for Hit-Finding and Optimization of Hepatitis C Virus (HCV) Inhibitors

Design and synthesis of l- and d-phenylalanine derived rhodanines with novel C5-arylidenes as inhibitors of HCV NS5B polymerase

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