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: Ana P Guimarães, Felipe R de Souza, Aline A Oliveira, Arlan S Gonçalves, Ricardo B de Alencastro, Teodorico C Ramalho, Tanos C C França
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 91 Pg. 72-90 (Feb 16 2015) ISSN: 1768-3254 [Electronic] France
• PMID: 25458183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Chemical References

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

Topics

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