Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox

Ana P Guimarães; Felipe R de Souza; Aline A Oliveira; Arlan S Gonçalves; Ricardo B de Alencastro; Teodorico C Ramalho; Tanos C C França

doi:10.1016/j.ejmech.2014.09.099

Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox

Eur J Med Chem. 2015 Feb 16:91:72-90. doi: 10.1016/j.ejmech.2014.09.099. Epub 2014 Oct 13.

Authors

Ana P Guimarães¹, Felipe R de Souza², Aline A Oliveira³, Arlan S Gonçalves⁴, Ricardo B de Alencastro⁵, Teodorico C Ramalho⁶, Tanos C C França⁷

Affiliations

¹ 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.
² 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.
³ São Carlos Institute of Chemistry, University of São Paulo, Avenida Trabalhador São-carlense, 400, CP 780, 13560-970 São Carlos, SP, Brazil.
⁴ Federal Institute of Education Science and Technology of Espirito Santo (IFES), Avenida Ministro Salgado Filho, S/N°, 29106-010 Vila Velha, ES, Brazil.
⁵ Laboratory of Molecular Modeling, Institute of Chemistry, Federal University of Rio de Janeiro, 21949-900 Rio de Janeiro, RJ, Brazil.
⁶ Laboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras (UFLA), 37200-000 Lavras, MG, Brazil. Electronic address: teo@dqi.ufla.br.
⁷ 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.

PMID: 25458183
DOI: 10.1016/j.ejmech.2014.09.099

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.

Keywords: Docking; Molecular dynamics; Smallpox; Thymidylate kinase; Variola virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acyclovir / analogs & derivatives*
Antiviral Agents / chemistry*
Catalytic Domain
Cidofovir
Cytosine / analogs & derivatives
Cytosine / chemistry
Drug Design
Humans
Kinetics
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Mutation
Nucleoside-Phosphate Kinase / antagonists & inhibitors*
Nucleoside-Phosphate Kinase / chemistry
Nucleoside-Phosphate Kinase / genetics
Organophosphonates / chemistry
Small Molecule Libraries / chemistry*
Smallpox / drug therapy
Smallpox / virology
Species Specificity
Structure-Activity Relationship
Thermodynamics
Variola virus / chemistry*
Variola virus / enzymology
Variola virus / genetics
Viral Proteins / antagonists & inhibitors*
Viral Proteins / chemistry
Viral Proteins / genetics

Substances

Antiviral Agents
Ligands
Organophosphonates
Small Molecule Libraries
Viral Proteins
Cytosine
Nucleoside-Phosphate Kinase
dTMP kinase
Cidofovir
Acyclovir