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如题！
原文地址：
http://fightaidsathome.scripps.edu/news/vol2.html
PDF版下载地址：
http://fightaidsathome.scripps.edu/news/vol2.pdf
FightAIDS@Home News
November 29th, 2006 — Volume 2
From Computer to Test Tube...
We have completed our first experiments. First results from FightAIDS@Home computations are now being tested in the laboratory.
As we approach World AIDS Day 2006, we would like to give an update on our work, and the research directions that we are planning. Recent news indicates that the AIDS pandemic is still very much with us, and in fact is growing again. The problem of drug resistance has become even more critical, since vaccine development has yet to provide a route to prevention and spread.
We have been running FightAIDS@Home on The World Community Grid for almost one year now, and have reached several important milestones. Our work is not finished, but we are greatly encouraged by the results that we are getting thanks to the help of our FightAIDS@Home members around the globe who have enabled this research.
As with all scientific research, we run experiments — only our experiments are run on computers. When we started out a year ago, we began our first experiment, screening a large library of diverse chemical compounds against a panel of "wild-type" and mutant HIV proteases, a major target of AIDS therapy. We called this "Stage 1a". That terminology implied a sequential process that is not precisely how our experiments proceed. In fact, like most researchers, we run several experiments at the same time. Thus we have decided to change how we describe our work on the World Community Grid to be in terms of the experiments that we are running.
Our first experiment finished running on the Grid last April. In that work, Experiment 1a, we screened about 2,000 diverse compounds from the National Institutes of Health NCI compound library against a panel of about 300 HIV protease structures derived from x-ray crystallography and from computational modeling. Â The results of this huge computation (several quadrillion energy evaluations), are now in hand, and have been analyzed in a preliminary fashion, by searching for the compounds whose average binding energy was the best across the most protease variants. We have now ordered and obtained the 40 top compounds from the NIH, and our wet lab collaborators have run assays of these compounds against wild type and several mutant proteases. About 5 of the 40 compounds show interesting activity in inhibiting the proteases. This work is continuing to see if any of these compounds show extraordinary promise.
In the meantime, we are pursuing more sophisticated analyses of the results of Experiment 1. This work takes several forms. A deeper analysis of the statistics of our dockings may result in other promising compounds that we did not detect in our first pass. Additionally, an analysis of the relationships between the strength of a compound docking and the kinds of drug-resistant mutant proteases that it docks to, may reveal important information about the relationship between the inhibitor and the mechanism of resistance. Also, the results of this first experiment are giving us valuable data on the reliability of our computational methods, and on the modeled structures that were included in our protease panel. We are using this data to improve our models and our algorithms.
While this analysis is being carried out, we are running three more experiments on the World Community Grid. Experiment 1b is an in depth look at the entire NCI compound library, which contains over 250,000 compounds. This is needed to determine if the original diversity library is complete enough to represent the much larger set of compounds. Â Even with the computational resources that our volunteers are providing, we cannot scan all possible mutants with these compounds, so we are picking only a few (wild type and some relevant mutants) to see if we uncover new compounds that are not in the diversity set. So far, we have completed the screening of the entire library against the wild-type protease.
Similarly in Experiment 2 we have looked at a different compound library containing over 500,000 distinct chemical compounds. We have completed screening this library against a wild-type protease. Narrowing down this library to those compounds that have reasonable activity against wild type, we will then screen those promising compounds against the panel of mutants.
Experiment 3 is a test of an improved method for our AutoDock code, where we allow some motion in the protease receptor as well as the ligand. This is an important step in increasing the accuracy of the resulting docking predictions, since both the protein receptor and the inhibitor can be flexible and change shape as they interact.
Experiment 4 involves looking for HIV protease inhibitors that work by a totally different mechanism than existing drugs. For this, we are screening the NCI library against the HIV protease monomer. Since HIV protease functions only when two identical chains of the protein come together, if we can prevent the chains (each one is termed a "monomer") from joining, we can disrupt its function. The parts of the monomer that are involved in the interface joining the two chains appears to be highly conserved, so if we can disrupt this interface with a drug, it may deter resistance by mutation. So far we have run about 50,000 dockings of the diversity set against 22 different monomer structures.
As we combine our computational results with experimental validation, our follow-on experiments will be to develop variations of the most promising compounds into libraries that we can screen against a panel of protease mutants. In this on-going work we will also incorporate our improved methodologies into the computational procedures that we run.
There are now three scientific papers in preparation that are the direct result of the work that we have done on FightAIDS@Home. Your contributions to this work are gratefully acknowledged. More importantly, your involvement in our attempts to develop better AIDS treatments and novel drug-development methodologies is greatly appreciated.
FightAIDS@Home新闻
2006年11月29日 卷二
从电脑到试管…
我们已经完成了第一个实验。FightAIDS@Home 运算的第一个结果现在正在实验室里进行测试。
在2006年世界艾滋病日到来时，我们想给我们工作，我们的研究方向和规划作个介绍。最近有消息表明，艾滋病离我们仍然非常近，实际上是在飞速增长。抗药性问题变得更加严重，由于疫苗研制工作尚未为预防和阻止蔓延提供任何有用的方法。
我们已经在World Community Grid上运行FightAIDS@Home近一年了，并达成了若干重要的里程碑。我们的工作还没有完成，但我们为现有的成果感到十分的鼓舞，我们要感谢帮助我们做这一项研究的FightAIDS@Home全球的用户。
如同所有的科学研究那样，我们的实验只是在电脑上进行。当我们在一年前开始时，我们就开始了第一个实验，针对治疗艾滋病的主要目标，一组"野生型"和"突变型"HIV病毒蛋白酶，从一个含有多种化合物的大型分子库中筛选有效分子。我们称之为"第一阶段A"。从名字看我们的实验并不是顺序完成的。其实，象大多数研究者，我们要同时进行多次实验。因此我们决定改由我们在World Community Grid正在运行的实验来描述我们的工作。
我们的首次试验，于去年4月完成运行。在这一工作中，实验1a，我们针对一组源自X射线晶体及计算模型的约有300个病毒蛋白酶结构，从国家卫生研究所的NCI分子化合物分子库中筛选出了约二千多个分子。这个庞大运算的结果(进行了几万亿次能量评估)，现在全部到手了，并已通过在所有的蛋白酶异性体中寻找平均结合能最大的化合物，进行了初步分析。我们已经从NIH订购，并取得了40个最好的化合物，我们的合作者和实验室已经针对若干野生型和突变型蛋白酶开始检测这些化合物。40种化合物中约有5种对病毒蛋白酶有抑制性。这项工作仍在继续，看看这些化合物有没有其它的功效。
同时，我们在对实验1 的结果进行更精密的分析。这项工作包含多种形式。更深层的计算结果统计分析可能发现其它我们在之前并未察觉的有效化合物。另外，分析分子结合强度和某种抗药性突变蛋白酶之间的关系，可以揭示出与抑制剂和抗药性机制之间的关系有关的资料。同时，这次实验的结果为我们的计算方法和被列入我们蛋白酶组的模型结构的可靠性提供了宝贵的数据支持。我们正在利用这些数据来改进我们的模型和计算方法。
在这项分析正在紧张进行的同时，我们正在World Community Grid上运行其它的三个实验。实验1B是深入研究整个NCI化合物分子库，其中含有超过25万种化合物。这需要确定原来的多样性分子库是否足以代表绝大多数的化合物。即使是我们的志愿者提供的强大的运算资源，也不足以扫描这些化合物的所有可能的突变，因此我们之前只选择少数的几个(野生型和相关的突变型)看看多样性分子库是否有未包含进的新化合物。到目前为止，针对野生型蛋白酶，我们已经完成了对整个分子库的筛选。
同样，实验2我们要检查另一个含有超过50万种不同分子的分子库。我们已经针对野生型蛋白酶完成了对这一分子库的筛选。把这个分子库中对野生型有活性的化合物选出，然后再针对突变型对那些化合物进行计算。
实验3是测试我们改进的AutoDock算法，允许蛋白酶受体即配基可以随意改变。这是一个重要步骤，可以提高计算结果的准确性，因为实际中当蛋白受体和抑制剂相互作用时会灵活的改变它们的形状。
实验4是通过一种与现有药物完全不同的工作机制寻找病毒蛋白酶抑制剂。为此，我们针对艾滋病毒蛋白酶单体对NCI分子库进行筛选。由于只有当两个相同的蛋白质链在一起时艾滋病病毒蛋白才能发挥功能，如果我们能防止连锁，就可以破坏其功能。单体中涉及到连接的接口似乎是高度稳定的，因此，如果我们能用药物破坏这个接口，它可以阻止抗药性突变。到目前为止，我们已经针对22个单体结构对多样性分子库进行了约五万多次对接计算。
一旦我们把计算结果和实验验证结构相结合，我们的后续试验将找到更多的有前途的化合物加入到针对一组突变型病毒蛋白酶的待筛选分子库中。此间我们将边计算边修改算法。
目前有三篇关于FightAIDS@Home已取得成果的科学论文正在准备中。非常感谢您对这项工作的贡献。更重要的是，十分感谢您帮助我们努力寻找更好的艾滋病治疗方法和新型艾滋病治疗药物。
A plot showing the predicted binding energy of the top-scoring ligands versus the various HIV Proteases from x-ray crystallographic experiments. The band of blue, green and yellow colors along the top are the clinically-approved protease inhibitors.
一幅图展示与各种来自X射线晶体实验的病毒蛋白酶的结合能预测中得分最高的分子。蓝、绿、黄色块的顶部是临床批准使用的蛋白酶抑制剂。
注：没想到会这么快出初步结果。可惜我机子太差，不能参加这个项目，希望大家能支持一下。
[ Last edited by vmzy on 2006-12-11 at 15:17 ] |
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发表于 2006-12-2 22:42:06
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