2,3-Dihydroxy-quinoxaline induces ATPase activity of Herpes Simplex Virus thymidine kinase

• Published in: FEBS letters 2014-01, Vol.588 (3), p.509-511
• Main Authors: Zeifman, Alexey A., Novikov, Fedor N., Stroylov, Victor S., Stroganov, Oleg V., Chilov, Ghermes G., Skoblov, Alexander Y., Miroshnikov, Anatoly I., Skoblov, Yuri S.
• Format: Article
• Language: English
• Subjects: 2,3-dihydroxy-quinoxaline; Acyclovir - therapeutic use; Adenosine Triphosphatases - chemistry; Catalysis; DHQ; Enzyme kinetic; Herpes simplex virus; Herpes Simplex Virus thymidine kinase; HSV-TK; Humans; Inhibition; Kinetics; Molecular docking; Phosphorylation - drug effects; Quinoxalines - pharmacology; Simplexvirus - drug effects; Simplexvirus - enzymology; thin layer chromatography; Thymidine kinase; Thymidine Kinase - antagonists & inhibitors; Thymidine Kinase - chemistry; TLC
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2013.12.017

•2,3-Dihydroxy-quinoxaline inhibits acyclovir phosphorylation by herpesvirus thymidine kinase.•2,3-Dihydroxy-quinoxaline promotes ATPase activity of herpesvirus thymidine kinase.•This promotion is dose-dependent and follows the Michaelis–Menten scheme.•We propose a kinetic scheme for the whole process that is consistent with the experimental data. 2,3-Dihydroxy-quinoxaline, a small molecule that promotes ATPase catalytic activity of Herpes Simplex Virus thymidine kinase (HSV-TK), was identified by virtual screening. This compound competitively inhibited HSV-TK catalyzed phosphorylation of acyclovir with Ki=250μM (95% CI: 106–405μM) and dose-dependently increased the rate of the ATP hydrolysis with KM=112μM (95% CI: 28–195μM). The kinetic scheme consistent with this experimental data is proposed.