title: New approaches to structure-based discovery of dengue protease inhibitors.
abstract: Dengue virus (DENV), a member of the family Flaviviridae, presents a tremendous threat to global health since an estimated 2.5 billion people worldwide are at risk for epidemic transmission. DENV infections are primarily restricted to sub-tropical and tropical regions; however, there is concern that the virus will spread into new regions including the United States. There are no approved antiviral drugs or vaccines to combat dengue infection, although DENV vaccines have entered Phase 3 clinical trials. Drug discovery and development efforts against DENV and other viral pathogens must overcome specificity, efficacy, safety, and resistance challenges before the shortage of licensed drugs to treat viral infections can be relieved. Current drug discovery methods are largely inefficient and thus relatively ineffective at tackling the growing threat to public health presented by emerging and remerging viral pathogens. This review discusses current and newly implemented structure-based computational efforts to discover antivirals that target the DENV NS3 protease, although it is clear that these computational tools can be applied to most disease targets.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Tomlinson
authors.forename: R D
authors.initials: RD
authors.lastname: Malmstrom
authors.forename: S J
authors.initials: SJ
authors.lastname: Watowich
mesh_terms: D000818:Animals; D017326:Clinical Trials, Phase III as Topic; D019295:Computational Biology / Q000379:methods; D003715:Dengue / Q000188:drug therapy*; D053059:Dengue Vaccines / Q000627:therapeutic use; D003716:Dengue Virus / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D055808:Drug Discovery; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012697:Serine Endopeptidases / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000085242:Viral Proteases
chemical_list: D053059:Dengue Vaccines; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases