title: Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox.
abstract: Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK.
authors.affiliation: Department of Chemistry, Federal University of Viçosa, Anenida P.H. Rolfs, S/N°, Centro, 36570-000 Viçosa, MG, Brazil; Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Praça General Tiburcio 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil.
authors.forename: Ana P
authors.initials: AP
authors.lastname: Guimarães
authors.affiliation: Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Praça General Tiburcio 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil.
authors.forename: Felipe R
authors.initials: FR
authors.lastname: de Souza
authors.affiliation: São Carlos Institute of Chemistry, University of São Paulo, Avenida Trabalhador São-carlense, 400, CP 780, 13560-970 São Carlos, SP, Brazil.
authors.forename: Aline A
authors.initials: AA
authors.lastname: Oliveira
authors.affiliation: Federal Institute of Education Science and Technology of Espirito Santo (IFES), Avenida Ministro Salgado Filho, S/N°, 29106-010 Vila Velha, ES, Brazil.
authors.forename: Arlan S
authors.initials: AS
authors.lastname: Gonçalves
authors.affiliation: Laboratory of Molecular Modeling, Institute of Chemistry, Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil.
authors.forename: Ricardo B
authors.initials: RB
authors.lastname: de Alencastro
authors.affiliation: Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 37200-000 Lavras, MG, Brazil. Electronic address: teo@dqi.ufla.br.
authors.forename: Teodorico C
authors.initials: TC
authors.lastname: Ramalho
authors.affiliation: Laboratory of Molecular Modeling Applied to the Chemical and Biological Defense, Military Institute of Engineering, Praça General Tiburcio 80, Urca, 22290-270 Rio de Janeiro, RJ, Brazil. Electronic address: tanos@ime.eb.br.
authors.forename: Tanos C C
authors.initials: TC
authors.lastname: França
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives*; D000998:Antiviral Agents / Q000737:chemistry*; D020134:Catalytic Domain; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009154:Mutation; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D063065:Organophosphonates / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D012899:Smallpox / Q000188:drug therapy / Q000821:virology; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D012901:Variola virus / Q000737:chemistry* / Q000201:enzymology / Q000235:genetics; D014764:Viral Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D008024:Ligands; D063065:Organophosphonates; D054852:Small Molecule Libraries; D014764:Viral Proteins; D003596:Cytosine; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D000077404:Cidofovir; D000212:Acyclovir
keywords: Docking; Molecular dynamics; Smallpox; Thymidylate kinase; Variola virus