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Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3

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Abstract

Alcohol dehydrogenase 3 (ADH3) has been assigned a role in nitric oxide homeostasis due to its function as an S-nitrosoglutathione reductase. As altered S-nitrosoglutathione levels are often associated with disease, compounds that modulate ADH3 activity might be of therapeutic interest. We performed a virtual screening with molecular dockings of more than 40,000 compounds into the active site of human ADH3. A novel knowledge-based scoring method was used to rank compounds, and several compounds that were not known to interact with ADH3 were tested in vitro. Two of these showed substrate activity (9-decen-1-ol and dodecyltetraglycol), where calculated binding scoring energies correlated well with the logarithm of the k cat/K m values for the substrates. Two compounds showed inhibition capacity (deoxycholic acid and doxorubicin), and with these data three different lines for specific inhibitors for ADH3 are suggested: fatty acids, glutathione analogs, and cholic acids.

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Abbreviations

ADH:

Alcohol dehydrogenase

GSNO:

S-Nitrosoglutathione

HMGSH:

S-Hydroxymethylglutathione

MC:

Monte Carlo

NO:

Nitric oxide

VS:

Virtual screening

12-HDA:

12-Hydroxydodecanoic acid

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Acknowledgments

This work was supported by grants from Karolinska Institutet and Linköping University.

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Author notes

  1. Claudia A. Staab

    Present address: Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, 24105, Kiel, Germany

Authors and Affiliations

  1. Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden

    Mikko Hellgren, Linus J. Östberg, Claudia A. Staab & Jan-Olov Höög

  2. IFM Bioinformatics, Linköping University, 581 83, Linköping, Sweden

    Jonas Carlsson & Bengt Persson

  3. Department of Cell and Molecular Biology, Karolinska Institutet, 171 77, Stockholm, Sweden

    Bengt Persson

Authors
  1. Mikko Hellgren
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  2. Jonas Carlsson
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  4. Claudia A. Staab
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Correspondence to Jan-Olov Höög.

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Hellgren, M., Carlsson, J., Östberg, L.J. et al. Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3. Cell. Mol. Life Sci. 67, 3005–3015 (2010). https://doi.org/10.1007/s00018-010-0370-2

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  • DOI: https://doi.org/10.1007/s00018-010-0370-2

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