Discovery of Novel Small
Molecule Inhibitors of Dengue
Viral NS2B-NS3 Protease Using Virtual Screening and Scaffold Hopping
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Abstract
By virtual screening, compound <b>1</b> was found
to be active
against NS2B-NS3 protease (IC<sub>50</sub> = 13.12 ± 1.03 μM).
Fourteen derivatives (<b>22</b>) of compound <b>1</b> were
synthesized, leading to the discovery of four new inhibitors with
biological activity. In order to expand the chemical diversity of
the inhibitors, small-molecule-based scaffold hopping was performed
on the basis of the common scaffold of compounds <b>1</b> and <b>22</b>. Twenty-one new compounds (<b>23</b>, <b>24</b>) containing quinoline (new scaffold) were designed and synthesized.
Protease inhibition assays revealed that 12 compounds with the new
scaffold are inhibitors of NS2B-NS3 protease. Taken together, 17 new
compounds were discovered as NS2B-NS3 protease inhibitors with IC<sub>50</sub> values of 7.46 ± 1.15 to 48.59 ± 3.46 μM,
and 8 compounds belonging to two different scaffolds are active to
some extent against DENV based on luciferase reporter replicon-based
assays. These novel chemical entities could serve as lead structures
for discovering therapies against DENV