Structure-Based Design of a Benzodiazepine Scaffold Yields a Potent Allosteric Inhibitor of Hepatitis C NS5B RNA Polymerase
Journal of Medicinal Chemistry2009Vol. 52(14), pp. 4099–4102
Citations Over TimeTop 11% of 2009 papers
Koen Vandyck, Maxwell D. Cummings, Origène Nyanguile, Carlo Boutton, Sandrine Vendeville, David C. McGowan, Benoit Devogelaere, Katie Amssoms, Stefaan Last, Klara Rombauts, Abdellah Tahri, Pedro Lory, Lili Hu, Derek A. Beauchamp, Kenny Simmen, Pierre Raboisson
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.
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