Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox: part II.

Abstract

Acknowledging the importance of studies toward the development of measures against terrorism and bioterrorism, this study aims to contribute to the design of new prototypes of potential drugs against smallpox. Based on a former study, nine synthetic feasible prototypes of selective inhibitors for thymidylate kinase from Variola virus (VarTMPK) were designed and submitted to molecular docking, molecular dynamics simulations and binding energy calculations. The compounds are simplifications of two more complex scaffolds, with a guanine connected to an amide or alcohol through a spacer containing ether and/or amide groups, formerly suggested as promising for the design of selective inhibitors of VarTMPK. Our study showed that, despite the structural simplifications, the compounds presented effective energy values in interactions with VarTMPK and HssTMPK and that the guanine could be replaced by a simpler imidazole ring linked to a -NH2 group, without compromising the affinity for VarTMPK. It was also observed that a positive charge in the imidazole ring is important for the selectivity toward VarTMPK and that an amide group in the spacer does not contribute to selectivity. Finally, prototype 3 was pointed as the most promising to be synthesized and experimentally evaluated. Communicated by Ramaswamy H. Sarma.

• Authors: Danielle Rodrigues Garcia, Felipe Rodrigues de Souza, Ana Paula Guimarães, Teodorico Castro Ramalho, Alcino Palermo de Aguiar, Tanos Celmar Costa França
• Journal: Journal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 37 Issue 17 Pg. 4569-4579 (10 2019) ISSN: 1538-0254 [Electronic] England
• PMID: 30488769 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Ligands
• Nucleoside-Phosphate Kinase
• dTMP kinase

Topics

• Drug Design
• Enzyme Inhibitors (chemistry, pharmacology, therapeutic use)
• Humans
• Ligands
• Molecular Docking Simulation
• Molecular Dynamics Simulation
• Nucleoside-Phosphate Kinase (antagonists & inhibitors, chemistry)
• Smallpox (drug therapy)
• Thermodynamics
• Variola virus (enzymology)