Exploring DNA topoisomerase I ligand space in search of novel anticancer agents.
Exploring DNA topoisomerase I ligand space in search of novel anticancer agents.
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DOI：
10.1371/journal.pone.0025150
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Griffith R
中科院分区：
文献类型：
--
作者：
Drwal MN;Agama K;Wakelin LP;Pommier Y;Griffith R
DNA拓扑异构酶I（Top1）在肿瘤细胞中过表达，是肿瘤化疗的重要靶点。它通过引入瞬时单链断裂并允许断裂的链围绕中间Top1 - DNA共价复合物旋转来松弛DNA加工过程中产生的DNA扭转应变。这种复合物可以被一组与DNA碱基和酶在切割位点相互作用的抗癌剂捕获，从而防止进一步的拓扑异构酶活性。在这里，我们已经确定了新的Top1抑制剂作为潜在的抗癌药物，通过使用基于结构和配体的分子建模方法的组合。药效团模型已开发的基础上的衍生物的生物碱喜树碱（CPT），这代表了有效的抗肿瘤药物和Top1抑制剂的主要群体的分子特征。所产生的模型用于国家癌症研究所（NCI，USA）化合物数据库的计算机筛选，从而鉴定出一组结构多样的分子。观察到这些分子中有几种已知的Top1抑制剂和针对人类肿瘤细胞系的细胞毒性药物，验证了该策略。通过对接到Top1 - DNA复合物的结合位点中，进一步评价了未测试的命中物抑制Top1活性的潜力，从而选择了10种化合物用于生物学测试。受化合物可用性的限制，已经在体外测试了7种化合物的Top1抑制活性，其中5种显示出轻度至中度的Top1抑制。通过活性化合物的相似性搜索发现的另一种化合物也显示出温和的活性。虽然测试的化合物只显示低的体外抗肿瘤活性，我们的方法已经成功地识别结构新颖的Top1抑制剂值得进一步研究作为潜在的抗癌药物。
DNA topoisomerase I (Top1) is over-expressed in tumour cells and is an important target in cancer chemotherapy. It relaxes DNA torsional strain generated during DNA processing by introducing transient single-strand breaks and allowing the broken strand to rotate around the intermediate Top1 – DNA covalent complex. This complex can be trapped by a group of anticancer agents interacting with the DNA bases and the enzyme at the cleavage site, preventing further topoisomerase activity. Here we have identified novel Top1 inhibitors as potential anticancer agents by using a combination of structure- and ligand-based molecular modelling methods. Pharmacophore models have been developed based on the molecular characteristics of derivatives of the alkaloid camptothecin (CPT), which represent potent antitumour agents and the main group of Top1 inhibitors. The models generated were used for in silico screening of the National Cancer Institute (NCI, USA) compound database, leading to the identification of a set of structurally diverse molecules. The strategy is validated by the observation that amongst these molecules are several known Top1 inhibitors and agents cytotoxic against human tumour cell lines. The potential of the untested hits to inhibit Top1 activity was further evaluated by docking into the binding site of a Top1 – DNA complex, resulting in a selection of 10 compounds for biological testing. Limited by the compound availability, 7 compounds have been tested in vitro for their Top1 inhibitory activity, 5 of which display mild to moderate Top1 inhibition. A further compound, found by similarity search to the active compounds, also shows mild activity. Although the tested compounds display only low in vitro antitumour activity, our approach has been successful in the identification of structurally novel Top1 inhibitors worthy of further investigation as potential anticancer agents.
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