Molecular dynamics simulations of Zika virus NS3 helicase: Insights into RNA binding site activity

The A–Z of Zika drug discovery

“…For instance, the accessible pocket(s) within the active site of the NS3h-RNA complex is relatively shallow, and previous efforts to discover specific inhibitors of DENV NS3h have been challenging [71]. A potential strategy to deal with these issues could involve targeting other sites of ZIKV NS3h, such as the putative allosteric site that we discovered in our MD simulations [72]. We are currently performing new VS against snapshots of ZIKV NS3h that we generated with MD to test this strategy.…”

“…MD simulations of NS3h where performed to study the proteins flexibility and conformations preferences [72]. This work showed that the RNA binding loop is influenced by the presence of the RNA strand, being more stable and in a closed conformation, when RNA is bound to the protein [72]. The different conformations observed during MD showed a distinct region beneath or behind the ATP site, which could perhaps be an allosteric site, and could help guide the discovery or design of new inhibitors.…”

“…The authors also suggest that suramin might inhibit the NS3h activity or might affect packaging by binding to positively charged residues on the capsid protein [75]. MD simulations of NS3h where performed to study the proteins flexibility and conformations preferences [72]. This work showed that the RNA binding loop is influenced by the presence of the RNA strand, being more stable and in a closed conformation, when RNA is bound to the protein [72].…”

Perspectives towards antiviral drug discovery against Ebola virus

“…Recently, MD simulations have been used to study the molecular behavior of ZIKV NS3‐helicase, both in the presence and absence of single‐stranded RNA, and the potential implications for NS3‐helicase activity/inhibition . Recent studies have reported notable examples of MD‐driven drug discovery .…”

“…For comparison purposes between MD‐refined complex systems, binding‐free energy calculations using the molecular mechanics Poisson‐Boltzmann surface area/generalized born surface area can be incorporated in the workflow. Like these, numerous recent studies have been performed with the aid of MD simulations in search of direct antivirals and investigating drug resistance mechanisms …”