Abstract
Zika virus (ZIKV), one of the flaviviruses, has attracted worldwide attention since its large epidemics around Brazil. Association of ZIKV infection with microcephaly and neurological problems such as Guillain–Barré syndrome has prompted intensive pathological investigations. However, there is still a long way to go on the discovery of effective anti-ZIKV therapeutics. In this study, an in silico screening of the National Cancer Institute (NCI) diversity set based on ZIKV NS3 helicase was performed using a molecular docking approach. Selected compounds with drug-like properties were subjected to cell-based antiviral assays resulting in the identification of two novel lead compounds (named Compounds 1 and 2). They inhibited ZIKV infection with IC50 values at the micro-molar level (8.5 μM and 15.2 μM, respectively). Binding mode analysis, absolute binding free energy calculation, and structure–activity relationship studies of these two compounds revealed their possible interactions with ZIKV NS3 helicase, suggesting a mechanistic basis for further optimization. These two novel small molecules may represent new leads for the development of inhibitory drugs against ZIKV.
Highlights
The rapid spread of Zika virus (ZIKV) infection has become a severe and escalating threat to global health
Crystal structures of ZIKV NS3 helicase in complex with single-stranded RNA and nucleoside triphosphate (NTP), respectively, have unveiled a molecular basis for RNA unwinding activities [16,32,33]. ssRNA runs across the central groove of each domain with the bases stacked against each other, while NTP binds the cleft between domains 1 and 2 [16,32,33]
We performed a virtual screening by docking small molecules from a compound library to ZIKV NS3Hel active sites including both RNA and NTP binding cavities (Figure 1)
Summary
The rapid spread of Zika virus (ZIKV) infection has become a severe and escalating threat to global health. ZIKV was first isolated in 1947 from a rhesus monkey around the Zika forest of Uganda [1]. It has not been paid much attention until 2015, when it rapidly remerged in at least 33 countries and territories [2,3], and became an expanding epidemic across Central and South America [4]. During 2015 and 2016, substantial evidence has confirmed its congenital, perinatal, and sexual transmission [6,7], and noted that ZIKV infection is directly associated with frightening neural diseases including Guillain–Barré syndrome [8] and congenital microcephaly [9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
