Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
Cell Mol Life Sci. 2010 Sep;67(17):3005-15. doi: 10.1007/s00018-010-0370-2. Epub 2010 Apr 20.
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.
由于醇脱氢酶 3（ADH3）具有作为 S-亚硝基谷胱甘肽还原酶的功能，因此被认为在一氧化氮动态平衡中发挥作用。由于 S-亚硝基谷胱甘肽水平的改变通常与疾病有关，因此调节 ADH3 活性的化合物可能具有治疗意义。我们使用分子对接对超过 40000 种化合物进行了人 ADH3 活性部位的虚拟筛选。使用新的基于知识的评分方法对化合物进行排序，并在体外测试了几种已知不与 ADH3 相互作用的化合物。其中两种显示出底物活性（9-癸烯-1-醇和十二烷基四乙二醇），计算出的结合评分能量与底物的 k（cat）/K（m）值的对数很好地相关。两种化合物显示出抑制能力（脱氧胆酸和阿霉素），根据这些数据，建议针对 ADH3 的三种不同类型的特异性抑制剂：脂肪酸、谷胱甘肽类似物和胆酸。
