Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents

[Display omitted] •Virtual screening to discover potential nucleic acids intercalators.•Two hits active against Vaccinia virus were found.•Intercalating mechanism was proposed for the hits. This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2017-08, Vol.27 (16), p.3915-3919
Main Authors: Klimenko, Kyrylo, Lyakhov, Sergey, Shibinskaya, Marina, Karpenko, Alexander, Marcou, Gilles, Horvath, Dragos, Zenkova, Marina, Goncharova, Elena, Amirkhanov, Rinat, Krysko, Andrei, Andronati, Sergei, Levandovskiy, Igor, Polishchuk, Pavel, Kuz'min, Victor, Varnek, Alexandre
Format: Article
Language:English
Subjects:
Antiviral activity
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cell Line
Cell Survival - drug effects
Chemical Sciences
Cheminformatics
DNA - drug effects
DNA affinity
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Humans
Microbial Sensitivity Tests
Molecular Structure
Quantitative Structure-Activity Relationship
Structure-activity modeling
Vaccinia virus
Vesicular stomatitis Indiana virus - drug effects
Virtual screening
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Summary:[Display omitted] •Virtual screening to discover potential nucleic acids intercalators.•Two hits active against Vaccinia virus were found.•Intercalating mechanism was proposed for the hits. This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2017.06.035