Abstract:
As a way to investigate new antiviral leads against Zika virus (ZIKV), we have targeted the NS3 helicase
(NS3H) protein with biscoumarin derivatives. The NS3H protein from ZIKV is important, as it plays a
significant role in the viral genome replication process. We have assessed the NTPase modulatory effects
of biscoumarin derivatives against the NTPase activity of NS3H through in vitro enzymatic studies. Subsequently,
to explore the mechanism, detailed computational studies were conducted. The NS3H protein has two binding
cavities: one is the NTPase binding cavity where ATP binds, and the other is an RNA binding cavity for the
binding of RNA molecules. Biscoumarin derivatives were found to be efficient in binding to both cavities, i.e., the
NTPase and RNA binding cavities of the NS3H protein. A biscoumarin derivative with the best binding affinity for
the NTPase binding cavity and the lowest binding affinity for the RNA binding groove revealed the best in vitro
NTPase inhibitory activity. Also, the biscoumarin derivative with the lowest binding affinity for the NTPase binding
cavity and higher binding affinity for the RNA binding cavity revealed the worst NTPase inhibitory activity under
the same in vitro assay conditions. Here, we concluded that biscoumarin derivatives are modulators of the NS3H
protein and they can be considered as promising anti-viral lead molecules. The structural activity relationships
(SARs) of the biscoumarin derivatives in relation to their NTPase inhibitory activities were established, and we
reported two derivatives, namely MN-9 and MN-10, as potential NS3H–NTPase inhibitor molecules.
