The discovery of Zika virus NS2B-NS3 inhibitors with antiviral activity via an integrated virtual screening approach
Document Type
Article
Publication Date
8-1-2022
Abstract
With expanding recent outbreaks and a lack of treatment options, the Zika virus (ZIKV) poses a severe health concern. The availability of ZIKV NS2B-NS3 co-crystallized structures paved the way for rational drug discovery. A computer-aided structure-based approach was used to screen a diverse library of compounds against ZIKV NS2B-NS3 protease. The top hits were selected based on various binding free energy calculations followed by perresidue decomposition analysis. The selected hits were then evaluated for their biological potential with ZIKV protease inhibition assay and antiviral activity. Among 26 selected compounds, 8 compounds showed promising activity against ZIKV protease with a percentage inhibition of greater than 25 and 3 compounds displayed similar to 50% at 10 mu M, which indicates an enrichment rate of approximately 36% (threshold IC50 < 10 mu M) in the ZIKV-NS2B-NS3 protease inhibition assay. Of these, only one compound (23) produced whole-cell anti-ZIKV activity, and the binding mode of 23 was extensively analyzed through long-run molecular dynamics simulations. The current study provides a promising starting point for the further development of novel compounds against ZIKV.
Keywords
Virtual screening, Zika virus, NS2B-NS3 protease, Flavivirus, Protease inhibitor
Divisions
CHEMISTRY
Funders
None
Publication Title
European Journal of Pharmaceutical Sciences
Volume
175
Publisher
Elsevier
Publisher Location
RADARWEG 29, 1043 NX AMSTERDAM, NETHERLANDS