title: Preventing the return of smallpox: molecular modeling studies on thymidylate kinase from Variola virus.
abstract: Smallpox was one of the most devastating diseases in the human history and still represents a serious menace today due to its potential use by bioterrorists. Considering this threat and the non-existence of effective chemotherapy, we propose the enzyme thymidylate kinase from Variola virus (VarTMPK) as a potential target to the drug design against smallpox. We first built a homology model for VarTMPK and performed molecular docking studies on it in order to investigate the interactions with inhibitors of Vaccinia virus TMPK (VacTMPK). Subsequently, molecular dynamics (MD) simulations of these compounds inside VarTMPK and human TMPK (HssTMPK) were carried out in order to select the most promising and selective compounds as leads for the design of potential VarTMPK inhibitors. Results of the docking and MD simulations corroborated to each other, suggesting selectivity towards VarTMPK and, also, a good correlation with the experimental data.
authors.affiliation: a Laboratory of Molecular Modeling Applied to Chemical and Biological Defense (LMACBD) , Military Institute of Engineering , Praça General Tibúrcio 80, Rio de Janeiro , 22290-270 , Brazil .
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Guimarães
authors.forename: Teodorico Castro
authors.initials: TC
authors.lastname: Ramalho
authors.forename: Tanos Celmar Costa
authors.initials: TC
authors.lastname: França
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D001665:Binding Sites; D001973:Bromodeoxyuridine / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding / Q000187:drug effects; D057927:Hydrophobic and Hydrophilic Interactions / Q000187:drug effects; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012899:Smallpox / Q000517:prevention & control*; D013816:Thermodynamics; D012901:Variola virus / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000596:Amino Acids; D047428:Protein Kinase Inhibitors; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D001973:Bromodeoxyuridine
keywords: Variola virus; docking; molecular dynamics; smallpox; thymidylate kinase