2 research outputs found
Multiple e‑Pharmacophore Modeling, 3D-QSAR, and High-Throughput Virtual Screening of Hepatitis C Virus NS5B Polymerase Inhibitors
The hepatitis C virus (HCV) NS5B
RNA-dependent RNA polymerase (RdRP)
is a crucial and unique component of the HCV RNA replication machinery
and a validated target for drug discovery. Multiple crystal structures
of NS5B inhibitor complexes have facilitated the identification of
novel compound scaffolds through in silico analysis. With the goal
of discovering new NS5B inhibitor leads, HCV NS5B crystal structures
bound with inhibitors in the palm and thumb allosteric pockets in
combination with ligands with known inhibitory potential were explored
for a comparative pharmacophore analyses. The energy-based and 3D-QSAR-based
pharmacophore models were validated using enrichment analysis, and
the six models thus developed were employed for high-throughput virtual
screening and docking to identify nonpeptidic leads. The hits derived
at each stage were analyzed for diversity based on the six pharmacophore
models, followed by molecular docking and filtering based on their
interaction with amino acids in the NS5B allosteric pocket and 3D-QSAR
predictions. The resulting 10 hits displaying diverse scaffold were
then screened employing biochemical and cell-based NS5B and anti-HCV
inhibition assays. Of these, two molecules H-5 and H-6 were the most
promising, exhibiting IC<sub>50</sub> values of 28.8 and 47.3 μM
against NS5B polymerase and anti-HCV inhibition of 96% and 86% at
50 μM, respectively. The identified leads comprised of benzimidazole
(H-5) and pyridine (H-6) scaffolds thus constitute prototypical molecules
for further optimization and development as NS5B inhibitors
Structure-Based Discovery of Pyrazolobenzothiazine Derivatives As Inhibitors of Hepatitis C Virus Replication
The
NS5B RNA-dependent RNA polymerase is an attractive target for
the development of novel and selective inhibitors of hepatitis C virus
replication. To identify novel structural hits as anti-HCV agents,
we performed structure-based virtual screening of our in-house library
followed by rational drug design, organic synthesis, and biological
testing. These studies led to the identification of pyrazolobenzothiazine
scaffold as a suitable template for obtaining novel anti-HCV agents
targeting the NS5B polymerase. The best compound of this series was
the <i>meta</i>-fluoro-<i>N</i>-1-phenyl pyrazolobenzothiazine
derivative <b>4a</b>, which exhibited an EC<sub>50</sub> = 3.6 μM, EC<sub>90</sub> = 25.6 μM,
and CC<sub>50</sub> > 180 μM in the Huh 9–13 replicon
system, thus providing a good starting point for further hit evolution