Structure-based design of a benzodiazepine scaffold yields a potent allosteric inhibitor of hepatitis C NS5B RNA polymerase.
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.
Vandyck
Koen
K
Tibotec BVBA, Generaal de Wittelaan L 11B 3, B-2800 Mechelen, Belgium.
Cummings
Maxwell D
MD
Nyanguile
Origène
O
Boutton
Carlo W
CW
Vendeville
Sandrine
S
McGowan
David
D
Devogelaere
Benoit
B
Amssoms
Katie
K
Last
Stefaan
S
Rombauts
Klara
K
Tahri
Abdellah
A
Lory
Pedro
P
Hu
Lili
L
Beauchamp
Derek A
DA
Simmen
Kenny
K
Raboisson
Pierre
P
D000494:Allosteric Regulation / Q000187:drug effects; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D008968:Molecular Conformation; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D001569:Benzodiazepines; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase