Abstract
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.
MeSH terms
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Antiviral Agents / chemical synthesis*
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Antiviral Agents / chemistry
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Binding Sites
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Crystallography, X-Ray
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Models, Molecular
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Molecular Conformation
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Proline / analogs & derivatives*
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Proline / chemical synthesis*
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Proline / chemistry
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Viral Nonstructural Proteins / antagonists & inhibitors*
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Viral Nonstructural Proteins / chemistry*
Substances
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Antiviral Agents
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Sulfonamides
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Viral Nonstructural Proteins
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Proline
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NS-5 protein, hepatitis C virus