Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova 17, SI-2000 Maribor, Slovenia.
Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000 Koper, Slovenia.
Biomolecules. 2021 Mar 23;11(3):479. doi: 10.3390/biom11030479.
Phosphodiesterase 4 (PDE4), mainly present in immune, epithelial, and brain cells, represents a family of key enzymes for the degradation of cyclic adenosine monophosphate (cAMP), which modulates inflammatory response. In recent years, the inhibition of PDE4 has been proven to be an effective therapeutic strategy for the treatment of neurological disorders. PDE4D constitutes a high-interest therapeutic target primarily for the treatment of Alzheimer's disease, as it is highly involved in neuroinflammation, learning ability, and memory dysfunctions. In the present study, a thorough computational investigation consisting of molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations based on the linear response approximation (LRA) method was performed to study dietary polyphenols as potential PDE4D inhibitors. The obtained results revealed that curcumin, 6-gingerol, capsaicin, and resveratrol represent potential PDE4D inhibitors; however, the predicted binding free energies of 6-gingerol, capsaicin, and resveratrol were less negative than in the case of curcumin, which exhibited the highest inhibitory potency in comparison with a positive control rolipram. Our results also revealed that the electrostatic component through hydrogen bonding represents the main driving force for the binding and inhibitory activity of curcumin, 6-gingerol, and resveratrol, while the van der Waals component through shape complementarity plays the most important role in capsaicin's inhibitory activity. All investigated compounds form hydrophobic interactions with residues Gln376 and Asn602 as well as hydrogen bonds with nearby residues Asp438, Met439, and Ser440. The binding mode of the studied natural compounds is consequently very similar; however, it significantly differs from the binding of known PDE4 inhibitors. The uncovered molecular inhibitory mechanisms of four investigated natural polyphenols, curcumin, 6-gingerol, capsaicin, and resveratrol, form the basis for the design of novel PDE4D inhibitors for the treatment of Alzheimer's disease with a potentially wider therapeutic window and fewer adverse side effects.
磷酸二酯酶 4（PDE4）主要存在于免疫、上皮和脑细胞中，是降解环磷酸腺苷（cAMP）的关键酶家族，cAMP 可调节炎症反应。近年来，抑制 PDE4 已被证明是治疗神经障碍的有效治疗策略。PDE4D 是一个高兴趣的治疗靶点，主要用于治疗阿尔茨海默病，因为它高度参与神经炎症、学习能力和记忆功能障碍。在本研究中，进行了一项全面的计算研究，包括分子对接、分子动力学（MD）模拟和基于线性响应近似（LRA）方法的结合自由能计算，以研究膳食多酚作为潜在的 PDE4D 抑制剂。研究结果表明，姜黄素、6-姜酚、辣椒素和白藜芦醇是潜在的 PDE4D 抑制剂；然而，6-姜酚、辣椒素和白藜芦醇的预测结合自由能不如姜黄素那么负，与阳性对照罗利普兰相比，姜黄素表现出最高的抑制效力。我们的研究结果还表明，通过氢键的静电成分是姜黄素、6-姜酚和白藜芦醇结合和抑制活性的主要驱动力，而通过形状互补的范德华成分在辣椒素的抑制活性中起着最重要的作用。所有研究的化合物都与残基 Gln376 和 Asn602 形成疏水性相互作用，并与附近的残基 Asp438、Met439 和 Ser440 形成氢键。研究天然化合物的结合模式因此非常相似；然而，它与已知的 PDE4 抑制剂的结合模式有很大的不同。四种研究天然多酚（姜黄素、6-姜酚、辣椒素和白藜芦醇）的分子抑制机制为设计新型 PDE4D 抑制剂治疗阿尔茨海默病奠定了基础，这些抑制剂具有潜在更宽的治疗窗口和更少的不良反应。
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