Pharmaceutical Sciences Division, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Centre for Natural Medicines Research, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK.
Bioorg Med Chem. 2010 Mar 15;18(6):2204-2218. doi: 10.1016/j.bmc.2010.01.070. Epub 2010 Feb 8.
Chinese herbs were screened for compounds which may be active against four targets involved in inflammation, using pharmacophore-assisted docking. Multiple LigandScout (LS) pharmacophores built from ligand-receptor complexes in the protein databank (PDB) were first employed to select compounds. These compounds were then docked using LS-derived templates and ranked according to docking score. The targets comprised cyclo-oxygenases 1 & 2 (COX), p38 MAP kinase (p38), c-Jun terminal-NH(2) kinase (JNK) and type 4 cAMP-specific phosphodiesterase (PDE4). The results revealed that multi-target inhibitors are likely to be relatively common in Chinese herbs. Details of their distribution are given, in addition to experimental evidence supporting these results. Examples of compounds predicted to be active against at least three targets are presented, and their features outlined. The distribution of herbs containing predicted inhibitors was also analysed in relation to 192 Chinese formulas from over 50 herbal categories. Among those found to contain a high proportion of these herbs were formulas traditionally used to treat fever, headache, rheumatoid arthritis, inflammatory bowel disorders, skin disease, cancer, and traumatic injury. Relationships between multi-target drug discovery and Chinese medicine are discussed.
采用基于药效团的对接方法，从四种参与炎症反应的靶点中筛选出可能具有活性的中草药化合物。首先利用蛋白质数据库（PDB）中配体-受体复合物构建的多配体 Scout（LS）药效团，选择化合物。然后使用 LS 衍生的模板对接这些化合物，并根据对接得分进行排序。这些靶点包括环氧化酶 1 和 2（COX）、p38MAP 激酶（p38）、c-Jun 末端-NH（2）激酶（JNK）和 4 型 cAMP 特异性磷酸二酯酶（PDE4）。结果表明，多靶点抑制剂在中草药中可能较为常见。除了支持这些结果的实验证据外，还给出了它们的详细分布情况。还预测了至少三种靶点的活性化合物，并概述了它们的特征。还分析了含有预测抑制剂的草药在 50 多种草药类别中的 192 种中草药配方中的分布情况。其中发现含有这些草药的配方包括传统上用于治疗发热、头痛、类风湿性关节炎、炎症性肠病、皮肤病、癌症和创伤性损伤的配方。讨论了多靶点药物发现与中药之间的关系。
