2. Academic Validation
  3. Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors

Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors

  • Bioorg Med Chem. 2016 Jun 1;24(11):2519-2529. doi: 10.1016/j.bmc.2016.04.018.
Birgit Viira 1,  Anastasia Selyutina 2,  Alfonso T García-Sosa 1,  Maarit Karonen 3,  Jari Sinkkonen 3,  Andres Merits 4,  Uko Maran 5
Affiliations

Affiliations

  • 1 Institute of Chemistry, University of Tartu, Tartu 50411, Estonia.
  • 2 Institute of Technology, University of Tartu, Tartu 50411, Estonia.
  • 3 Department of Chemistry, University of Turku, FI-20014 Turku, Finland.
  • 4 Institute of Technology, University of Tartu, Tartu 50411, Estonia. Electronic address: andres.merits@ut.ee.
  • 5 Institute of Chemistry, University of Tartu, Tartu 50411, Estonia. Electronic address: uko.maran@ut.ee.
PMID: 27108399 DOI: 10.1016/j.bmc.2016.04.018
Abstract

A set of top-ranked compounds from a multi-objective in silico screen was experimentally tested for toxicity and the ability to inhibit the activity of HIV-1 Reverse Transcriptase (RT) in cell-free assay and in cell-based assay using HIV-1 based virus-like particles. Detailed analysis of a commercial sample that indicated specific inhibition of HIV-1 reverse transcription revealed that a minor component that was structurally similar to that of the main compound was responsible for the strongest inhibition. As a result, novel s-triazine derivatives were proposed, modelled, discovered, and synthesised, and their Antiviral activity and cellular toxicity were tested. Compounds 18a and 18b were found to be efficient HIV-1 RT inhibitors, with an IC50 of 5.6±1.1μM and 0.16±0.05μM in a cell-based assay using infectious HIV-1, respectively. Compound 18b also had no detectable toxicity for different human cell lines. Their binding mode and interactions with the RT suggest that there was strong and adaptable binding in a tight (NNRTI) hydrophobic pocket. In summary, this iterative study produced structural clues and led to a group of non-toxic, novel compounds to inhibit HIV-RT with up to nanomolar potency.

Keywords

Antiviral activity; HIV; Molecular docking; Non-nucleoside reverse transcriptase inhibitors; Synthesis.

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