Abstract：
Modified nucleotides are ubiquitous with RNAs, also in contact with drugs that target the ribosome. Whether this represents a stabilization of the drug-ribosome complex, thus affecting the drug\'s affinity and possibly also intrinsic efficacy, remains an open question, however. The challenge of answering this question has been taken here with the only human-ribosome-targeting small-molecule currently in clinical use, the antitumor plant alkaloid homoharringtonine (HHT). The approach consisted in dissecting HHT-nucleotide interaction energies from QM-MM simulations in explicit water. What emerged is a network of mostly weak interactions of the large, branched HHT with standard nucleotides and a single modified nucleotide, out of the four ones present at PCT\'s A site. This is unlike the case of the small, compact marine antitumor alkaloid agelastatin A, which displays only a few, albeit strong, interactions with site-A ribosome nucleotides. This should aid tailoring drugs targeting the ribosome.
摘要：
修饰的核苷酸普遍存在于RNA中。也与靶向核糖体的药物接触。这是否代表药物-核糖体复合物的稳定，从而影响药物的亲和力和可能的内在功效，仍然是一个悬而未决的问题，however.回答这个问题的挑战是目前临床使用的唯一靶向人类核糖体的小分子，抗肿瘤植物生物碱高三尖杉酯碱（HHT）。该方法包括从显式水中的QM-MM模拟中解剖HHT-核苷酸相互作用能。出现的是一个主要是弱相互作用的网络，具有标准核苷酸和单个修饰核苷酸的分支HHT，在PCT的A站点中存在的四个。这与小的情况不同，紧凑型海洋抗肿瘤生物碱agelastinA，只显示几个，虽然强大，与位点A核糖体核苷酸的相互作用。这应该有助于定制靶向核糖体的药物。p{页边距-底部:0.25cm;方向:ltr;颜色:#000000;行高:115%;文本对齐:左;孤儿:2;寡妇:2;背景:透明}p.western{font-family:\"TimesNewRoman\",衬线；字体大小：11pt；so-language：en-US}p.cjk{font-family:\"DejaVuSans\";font-size:11pt;so-language:zh-CN}p.ctl{font-family:\"DejaVuSans\";font-size:12pt;so-language:hi-IN}a:link{color:#000080;so-language:zxx;text-demoration:underline}。
