Benzofuran-2-carboxylic acid

Small-molecule hit  that bind weakly (K_D ~ 6.4±0.6 mM) to substrate binding sites of the NS4A-bound NS3 protease of the hepatitis C virus (HCV).

OTAVAchemicals Catalogue Number:   0125160292

CAS Registry Number: 496-41-3

Purity: 98%

Ref.: Wyss et al. Non-Peptidic Small-Molecule Inhibitors of the Single-Chain Hepatitis C Virus NS3 Protease/NS4A Cofactor Complex Discovered by Structure-Based NMR Screening. J. Med. Chem. (2004), 47, 2486-2498.

Abstract: NMR-based screening of a customized fragment library identified 16 small-molecule hits that bind weakly (K_D ≈ 100 μM to 10 mM) to substrate binding sites of the NS4A-bound NS3 protease of the hepatitis C virus (HCV). Analogues for five classes of NMR hits were evaluated by a combination of NMR and biochemical data yielding SAR and, in most cases, optimized hits with improved potencies (K_D ≈ K_I ≈ 40 μM to 1 mM). NMR chemical shift perturbation data were used to establish the binding location and orientation of the active site directed scaffolds in these five analogue series. Two of these scaffolds, which bind the enzyme at the proximal S1 S3 and S2′ substrate binding sites, were linked together producing competitive inhibitors of the HCV NS3 protease with potencies in the micromolar range. This example illustrates that the low molecular weight scaffolds discovered from structure-based NMR screening can be optimized with focused structure-guided chemistry to produce potent nonpeptidic small- molecule inhibitors of the HCV NS3 protease.