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

• Published in: Cellular and molecular life sciences : CMLS 2010, Vol.67 (17), p.3005-3015
• Main Authors: Hellgren, Mikko, Carlsson, Jonas, Östberg, Linus J, Staab, Claudia A, Persson, Bengt, Höög, Jan-Olov
• Format: Article
• Language: English
• Subjects: Alcohol; Alcohol dehydrogenase; Alcohol Dehydrogenase - chemistry; Alcohol Dehydrogenase - isolation & purification; Alcohol Dehydrogenase - metabolism; Binding sites; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Chemical compounds; Dehydrogenase; Enzyme kinetics; Humans; Inhibitor drugs; Inhibitors; Kinetics; Life Sciences; Ligands; Medicin och hälsovetenskap; Models, Molecular; Molecular biology; Molecular docking; Molecular Structure; Nitric oxide; Protein Binding; Research Article; S-Nitrosoglutathione; TECHNOLOGY; TEKNIKVETENSKAP; Virtual screening
• ISSN: 1420-682X; 1420-9071; 1420-9071
• 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 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.