A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Design, discovery, modelling, synthesis, and biological evaluation of novel and small, low toxicity s-triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors
Tekijät: Viira B, Selyutina A, Garcia-Sosa AT, Karonen M, Sinkkonen J, Merits A, Maran U
Kustantaja: PERGAMON-ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2016
Journal: Bioorganic and Medicinal Chemistry
Tietokannassa oleva lehden nimi: BIOORGANIC & MEDICINAL CHEMISTRY
Lehden akronyymi: BIOORGAN MED CHEM
Vuosikerta: 24
Numero: 11
Aloitussivu: 2519
Lopetussivu: 2529
Sivujen määrä: 11
ISSN: 0968-0896
DOI: https://doi.org/10.1016/j.bmc.2016.04.018
Tiivistelmä
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 +/- 1.1 mu M and 0.16 +/- 0.05 mu M 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. (C) 2016 Elsevier Ltd. All rights reserved.
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 +/- 1.1 mu M and 0.16 +/- 0.05 mu M 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. (C) 2016 Elsevier Ltd. All rights reserved.
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