The severe health consequences that can occur as a result of infection by Zika virus underscores the importance of developing therapeutic agents capable of preventing the spread of infection. In this work, we leverage experience gained studying HIV and Ebola, to identify compounds capable of blocking viral-host membrane fusion through targeting Zika glycoprotein E. The DOCK6 suite of programs was used to perform a large-scale virtual screen through sampling and scoring conformations of candidate inhibitors in the context of an all atom molecular model of glycoprotein E created from a homologous viral entry protein in Dengue virus. To date, 240 compounds have been purchased targeting two out of four putative binding sites identified on the surface of the glycoprotein E complex. Experimental testing (cell viability, caspase activity & TCID50 assays) and additional computational analysis (molecular dynamics simulations & free energy calculations) has led to the identification of 6 compounds with promising inhibitory properties. Strategies to target the remaining sites, and optimize the initial experimentally-verified hits using a new de novo design version of DOCK, will also be presented.  <br/>

Identification and characterization of small molecule inhibitors of Zika virus glycoprotein E

2019 Fall National Meeting

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