Biscoumarin scaffold as an efficient anti-Zika virus lead with NS3-Helicase inhibitory potential: in-vitro and in-silico Investigation

As a way to investigate newer antiviral leads against Zika Virus (ZIKV), we have targeted NS3 helicase (NS3H) proteins by bis-coumarins derivatives. The NS3H protein from ZIKV is important, has a significant role in the viral genome replication process. We have assessed the NTPase modulatory effect of bis-coumarin derivatives against the NTPase activity of NS3H through in vitro enzymatic studies. Subsequently, to explore the mechanism, detailed computational studies were conducted. NS3H protein has two binding cavities, one is NTPase binding cavity where ATP binds and other is RNA binding cavity, for the binding of RNA molecule. Bis-coumarin derivatives were found efficient in binding against both the cavities, i.e. NTPase and RNA binding cavity of NS3H protein. A biscoumarin derivative with best binding affinity against the NTPase binding cavity and least binding affinity against RNA binding groove revealed the best in vitro NTPase inhibitory activity. However, a biscoumarin derivative with the least binding affinity against the NTPase binding cavity and higher binding affinity against the RNA binding cavity revealed the least NTPase inhibitory activity under the same in vitro assay. Here, we concluded that the biscoumarin derivatives are the modulators of NS3H protein and can be considered as promising anti-viral lead molecules. The structural activity relationship (SAR) of biscoumarin derivatives for NTPase inhibitory activity was established and we reported two derivatives namely MN-9, and MN-10 as potential NS3H-NTPase inhibitors molecules.