title: Structural Insight into NS5 of Zika Virus Leading to the Discovery of MTase Inhibitors.
abstract: Zika virus (ZIKV) is an emerging mosquito-borne virus recently linked to intrauterine growth restriction including abnormal fetal brain development. The recent outbreak of ZIKV reached pandemic level resulting in an alarming public health emergency. At present, there is limited understanding of the infectious mechanism and no approved therapy. Nonstructural protein 5 is essential for capping and replication of viral RNA and comprises a methyltransferase (MTase) and RNA dependent RNA polymerase domain. Here we used molecular modeling to obtain the structure of ZIKV MTase and molecular docking to identify the additional hydrophobic region uniquely conserved in flavivirus MTase that can be used as a druggable site. Subsequently, a virtual screening with a library of 28 341 compounds identified 10 best hits showing decisive contacts with the MTase. In vitro efficacy analysis of these compounds against ZIKV, by plaque reduction assay, has confirmed four of the top scored ligands (Life Chemicals ID: F3043-0013, F0922-0796, F1609-0442, and F1750-0048) having EC50 (50% effective concentration) values of 4.8 ± 2.3, 12.5 ± 7.4, 17.5 ± 8.4, and 17.6 ± 3.1 μM respectively, identifying lead compounds for anti-ZIKV drug development.
authors.affiliation: Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University , Québec City, Québec G1V 4G2, Canada.
authors.forename: Preyesh
authors.initials: P
authors.lastname: Stephen
authors.affiliation: Axe Infectious Disease, CHU Research Center and Laval University , Québec City, Québec G1V 4G2, Canada.
authors.forename: Mariana
authors.initials: M
authors.lastname: Baz
authors.affiliation: Axe Infectious Disease, CHU Research Center and Laval University , Québec City, Québec G1V 4G2, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
authors.affiliation: Axe Molecular Endocrinology and Nephrology, CHU Research Center and Department of Molecular Medicine, Laval University , Québec City, Québec G1V 4G2, Canada.
authors.forename: Sheng-Xiang
authors.identifier: 0000-0001-9149-375X
authors.initials: SX
authors.lastname: Lin
mesh_terms: D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008958:Models, Molecular; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000494:pharmacology*; D000071244:Zika Virus / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; D008780:Methyltransferases