In silico pharmacology suggests ginger extracts may reduce stroke risks
In silico pharmacology suggests ginger extracts may reduce stroke risks
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DOI：
10.1039/c1mb05228d
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发表时间：
2011-01-01
影响因子：
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通讯作者：
Chen, Calvin Yu-Chian
中科院分区：
文献类型：
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作者：
Chang, Tung-Ti;Chen, Kuan-Chung;Chen, Calvin Yu-Chian
环磷酸腺苷(CAMP)信号级联中的异常与与中风或心血管疾病风险相关的过敏反应有关。磷酸二酯酶4D(PDE4D)高度参与cAMP的调节，因此被认为是预防中风的潜在药物靶点。为了从中药中筛选潜在的PDE4D抑制剂，我们利用机器学习建模技术筛选了一个全面的中药数据库。建立的多元线性回归模型和支持向量机模型的相关系数分别为0.8234和0.7854。根据预测模型，从生姜家族中识别出三个候选基因。分子动力学模拟进一步验证了各候选化合物与对照抑制剂L-454560的结合稳定性。分子间距离表明候选分子可能会阻碍PDE4D与cAMP的结合。此外，Hypogen验证表明TOP2、TOP3和对照L-454560与预测的药效团相对应。结果表明，从生姜中分离得到的3个化合物均能抑制PDE4D对cAMP的结合和水解作用。我们进一步鉴定和表征了与PDE4D抑制相关的配体结合特性。
Aberrations in cyclic adenosine monophosphate (cAMP) signaling cascade has been linked to the allergic responses that associate with the risks of stroke or cardiovascular diseases. Phosphodiesterase 4D (PDE4D) has been shown to be highly involved in cAMP regulation and is hence implied to be a potential drug target in stroke prevention. To identify potential PDE4D inhibitors from traditional Chinese medicine (TCM), we employed machine learning modeling techniques to screen a comprehensive TCM database. The multiple linear regression (MLR) and support vector machine (SVM) models constructed have correlation coefficients of 0.8234 and 0.7854 respectively. Three candidates from the ginger family were identified based on the prediction models. Molecular dynamics simulation further validated the binding stabilities of each candidate in comparison to the control inhibitor L-454560. The intermolecular distances suggested that the candidates could hinder PDE4D from binding to cAMP. Furthermore, the HypoGen validation suggested that top2, top3, and the control L-454560 mapped with the predicted pharmacophores. The results suggested that the 3 compounds identified from the ginger family were capable in inhibiting cAMP binding and hydrolysis by PDE4D. We further identified and characterized the ligand binding properties that are associated with the inhibition of PDE4D.