title: Structure-assisted discovery of Variola major H1 phosphatase inhibitors.
abstract: Variola major virus, the causative agent of smallpox, encodes the dual-specificity H1 phosphatase. Because this enzyme is essential for the production of mature virus particles, it is an attractive molecular target for the development of therapeutic countermeasures for this potential agent of bioterrorism. As a first step in this direction, the crystal structure of H1 phosphatase has been determined at a resolution of 1.8 A. In silico screening methods have led to the identification of several small molecules that inhibit Variola H1 phosphatase with IC(50) values in the low micromolar range. These molecules provide novel leads for future drug development.
authors.affiliation: Macromolecular Crystallography Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, PO Box B, Frederick, MD, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Phan
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Tropea
authors.forename: David S
authors.initials: DS
authors.lastname: Waugh
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013045:Species Specificity; D055672:Static Electricity; D012901:Variola virus / Q000187:drug effects / Q000201:enzymology*; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D014764:Viral Proteins; D017027:Protein Tyrosine Phosphatases