School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan, ROC.
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan, ROC.
Bioorg Chem. 2020 Nov;104:104166. doi: 10.1016/j.bioorg.2020.104166. Epub 2020 Aug 25.
ALDH2, a key enzyme in the alcohol metabolism process, detoxifies several kinds of toxic small molecular aldehydes, which induce severe organ damages. The development of novel Alda-1 type ALDH2 activators was mostly relied on HTS but not rational design so far. To clarify the structure-activity relationship (SAR) of the skeleton of Alda-1 analogs by synthesis of the least number of analogs, we prepared 31 Alda-1 analogs and 3 isoflavone derivatives and evaluated for their ALDH2-activating activity. Among these, the ALDH2-activating activity of mono-halogen-substituted (Cl and Br) N-piperonylbenzamides 3b and 3 k, and non-aromatic amides 8a-8c, were 1.5-2.1 folds higher than that of Alda-1 at 20 μM. The relationship between binding affinity in computer aided molecular docking model and the ALDH2-activating activity assays were clarified as follows: for Alda-1 analogs, with the formation of halogen bonds, the enzyme-activating activity was found to follow a specific regression curve within the range between -5 kcal/mol and -4 kcal/mol. For isoflavone derivatives, the basic moiety on the B ring enhance the activating activity. These results provide a new direction of utilizing computer-aided modeling to design novel ALDH2 agonists in the future.
ALDH2 是酒精代谢过程中的关键酶，可解毒多种有毒的小分子醛，这些醛会导致严重的器官损伤。新型 Alda-1 型 ALDH2 激活剂的开发主要依赖于高通量筛选，而不是合理设计。为了通过最少数量的类似物合成来阐明 Alda-1 类似物骨架的结构-活性关系（SAR），我们制备了 31 种 Alda-1 类似物和 3 种异黄酮衍生物，并评估了它们对 ALDH2 的激活活性。在这些类似物中，单卤代（Cl 和 Br）N-胡椒基苯甲酰胺 3b 和 3k，以及非芳酰胺 8a-8c 的 ALDH2 激活活性在 20 μM 时比 Alda-1 高 1.5-2.1 倍。通过计算机辅助分子对接模型阐明了结合亲和力与 ALDH2 激活活性测定之间的关系如下：对于 Alda-1 类似物，在形成卤键的情况下，酶激活活性在-5 kcal/mol 到-4 kcal/mol 的范围内发现遵循特定的回归曲线。对于异黄酮衍生物，B 环上的碱性部分增强了激活活性。这些结果为未来利用计算机辅助建模设计新型 ALDH2 激动剂提供了新的方向。
