Zika Virus Therapeutic Lead Compounds Discovery Using Chemoinformatics Approaches

The Zika virus disease (ZVD) currently spreading around the globe has no known treatment available. A database of Zika-related genes (N=69) was subjected to chemoinformatics approaches using the canSAR protein annotation tool. Ligand-based druggability analysis of the database of genes identified thirtyfive druggable targets encompassing adhesion molecules, cytokines, enzymes, growth factors and receptors. Eight of these proteins (CCR5, HLA-DRB1, IL6, LTA, PLAT, PPIB, TNF and VEGFA) are current drug targets. Active (IC50< 100nM) Rule of Five (RO5) compliant and toxicophore negative CHEMBL compounds were identified for nine of these Zika virus lead targets (AXL, CASP1, CCL2, CCR5, CTSS, CXCL8, EIF2AK2, NPM1 and TYRO3). The AXL lead gene is a target for an FDA approved antineoplastic kinase inhibitor (Crizotinib/Xalkor). Another FDA approved kinase inhibitor for neoplasms; (Gefitinib) targets the EIF2AK2 lead protein. The protein targets (AXL, CASP1, CCR5, CTSS and RAF1) had highly bioactive compounds available (IC50 <1nM). CHEMBL compounds with unique protein target specificity were identified for AXL, CCL2, CCR5, CASP1, CTSS, CXCL8/IL8, NPM1/ALK and TYRO3. The RO5 compliant and toxicophore-negative lead compounds identified in the study offer a rationale for rapid verification in Zika virus cell culture models for drug discovery.