Druggableness of the Ebola Associated Genes in the Human Genome: Chemoinformatics Approaches

2016

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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 (IC 50 <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.

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Section: Methodsmentioning

confidence: 99%

“…The lead compounds can be rapidly tested in cell culture models, enabling accelerated drug discovery. Utilizing such an approach, recently lead compounds for Ebola virus, were discovered [33,34].…”

Section: Introductionmentioning

confidence: 99%

Zika Virus Therapeutic Lead Compounds Discovery Using Chemoinformatics Approaches

2016

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“…The bioinformatics and proteomics tools used in the study have been described. [35][36][37] The GWAS catalogue 38 and the NCBI Phenome-Genome Integrator, PheGenI 39 were used to create a working list of VAG. Characterization of the VAG was performed using the GeneALaCart, GeneAnalytics and VarElect data mining tools from the GeneCards.…”

Section: Methodsmentioning

confidence: 99%

“…[62][63][64] A powerful example of this concept was recently demonstrated for the Ebola virus disease therapeutics. 36,65 Association of genes with multiple diseases opens up avenues for expanding the repurposing strategy. Hence, the 51 Vitiligo genes were screened against the drug bank of compounds using the GeneALaCart Meta analysis tool of the GeneCards.…”

Section: Drug Bank Compounds For the Vitiligo Genesmentioning

confidence: 99%

Druggable Vitiligo Genome: A Fast Track Approach to Take the Genome Wide Association to the Clinic

2015

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“…38,41 The GeneAnalytics Gene Analysis tool was used to categorize results into lists of matched tissues, cells, diseases, pathways, compounds and gene ontology (GO) terms to enhance gene set interpretation. Associations between genes and diseases/ phenotypes based on shared pathways, interaction networks and paralogy relations were inferred using the VarElect NGS Phenotyper of the GeneCards Suite.…”

Section: Knowledge Databasesmentioning

confidence: 99%

Zika virus Therapeutics: Drug Targets and Repurposing Medicine from the Human Genome

2016

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