COMPUTER-ASSISTED MOLECULAR MODELING OF TUMOR PROMOTERS - RATIONALE FOR THE ACTIVITY OF PHORBOL ESTERS, TELEOCIDIN-B, AND APLYSIATOXIN
COMPUTER-ASSISTED MOLECULAR MODELING OF TUMOR PROMOTERS - RATIONALE FOR THE ACTIVITY OF PHORBOL ESTERS, TELEOCIDIN-B, AND APLYSIATOXIN
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DOI：
10.1073/pnas.83.2.241
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发表时间：
1986-01-01
影响因子：
11.1
通讯作者：
LISKAMP, RMJ
中科院分区：
文献类型：
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作者：
JEFFREY, AM;LISKAMP, RMJ
在皮肤癌发生的两阶段模型中，据信引发剂与DNA结合，而肿瘤促进剂如佛波醇12-十四烷酸酯13-乙酸酯（TPA）与膜相关的高亲和力受体（可能是蛋白激酶C）非共价结合。另外两种有效的促肿瘤物质，阿氏藻毒素和杀鱼素，似乎也通过结合和激活蛋白激酶C来起作用，尽管它们的化学结构完全不同。因此，我们对这三种化学类型的肿瘤促进剂中各种官能团的空间关系进行了计算机建模，试图解释这些不同的结构如何与相同的受体分子结合。我们提出了一个立体化学模型，其中TPA中C-3，C-4，C-9和C-20（O-3，O-4，O-9和O-20）的氧分别对应于teleocidin中的O-11，N-13，N-1和O-24位置和aperossiatoxin中的O-27，O-3，O-11和O-30氧。在该模型中，相对于相应原子的重叠的所有距离都< 1埃。此外，所有三种类型的分子都具有在相似位置取向的疏水部分。该模型进一步讨论了显示不同程度的肿瘤促进剂活性的其他化合物，包括美泽瑞因、巨大戟二萜醇和4 α-羟基苯丙氨酸。TPA。该模型解释了化学上不同的结构如何具有与肿瘤启动子相似的生物活性，并为设计肿瘤启动子的激动剂和拮抗剂提供了基础。
In the two-stage model of skin carcinogenesis, it is believed that initiators bind to DNA and that tumor promoters such as phorbol 12-tetradecanoate 13-acetate (TPA) bind noncovalently to membrane-associated high-affinity receptors, probably protein kinase C. Two other types of potent tumor-promoting substances, aplysiatoxin and teleocidin, appear to act also by binding to and activating protein kinase C, even though their chemical structures are quite different. Therefore, we have undertaken computer modeling of the spacial relationship of various functional groups in these three chemical classes of tumor promoters in an attempt to explain how these diverse structures bind to the same receptor molecule. We propose a stereochemical model in which the oxygens in TPA at C-3, C-4, C-9 and C-20 (O-3, O-4, O-9, and O-20) correspond to the O-11, N-13, N-1, and O-24 positions in teleocidin and the O-27, O-3, O-11, and O-30 oxygens in aplysiatoxin, respectively. In this model all distances with respect to overlap of the corresponding atoms are < 1 .ANG.. In addition, all three types of molecules have their hydrophobic moieties oriented in a similar position. This model is further discussed with respect to other compounds showing various degrees of activity as tumor promoters, including mezerein, ingenol, and 4.alpha.-TPA. The model explains how chemically diverse structures can have similar biological activity as tumor promoters and provides a basis for designing both agonists and antagonists of tumor promoters.