Abstract
HCV NS5B polymerase, an essential and virus-specific enzyme, is an important target for drug discovery. Using structure-based design, we optimized a 1,5-benzodiazepine NS5B polymerase inhibitor chemotype into a new sulfone-containing scaffold. The design yielded potent inhibitor (S)-4c (K(D) = 0.79 nM), which has approximately 20-fold greater affinity for NS5B than its carbonyl analogue (R)-2c.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Allosteric Regulation / drug effects
-
Benzodiazepines / chemistry*
-
Benzodiazepines / pharmacology*
-
Crystallography, X-Ray
-
Drug Design*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology
-
Hepacivirus / enzymology*
-
Models, Molecular
-
Molecular Conformation
-
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
-
RNA-Dependent RNA Polymerase / chemistry
-
RNA-Dependent RNA Polymerase / metabolism
-
Viral Nonstructural Proteins / antagonists & inhibitors*
-
Viral Nonstructural Proteins / chemistry
-
Viral Nonstructural Proteins / metabolism
Substances
-
Enzyme Inhibitors
-
Viral Nonstructural Proteins
-
Benzodiazepines
-
NS-5 protein, hepatitis C virus
-
RNA-Dependent RNA Polymerase