Enrichment of ligands with molecular dockings and subsequent characterization for human alcohol dehydrogenase 3
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- Hellgren, M., Carlsson, J., Östberg, L.J. et al. Cell. Mol. Life Sci. (2010) 67: 3005. doi:10.1007/s00018-010-0370-2
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 kcat/Km 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.
KeywordsAlcohol dehydrogenaseEnzyme kineticsInhibitorsMolecular dockingS-NitrosoglutathioneVirtual screening