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发表于 2006-4-29 21:43:05
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[谢绝灌水]FAAH新闻贴！
虽然FAAH的科学家比较喜欢埋头苦干，很少发新闻。但还是开个新闻贴好了，以备不时之需。
"World Community Grid Completes First Stage of FightAIDS@Home
By Prof. Arthur J. Olson, Ph.D., Dr. Garrett M. Morris, M.A. (Oxon.), D.Phil. (Oxon),
Dr. William M. Lindstrom, Jr., Ph.D., & Alexandre Gillet, The Scripps Research Institute
World Community Grid has already achieved a significant milestone on FightAIDS@Home, completing Stage 1a of the project, which was launched in November, 2005.
The National Cancer Institute (NCI) maintains a database of chemical compounds, many of which are available as actual samples for testing in test tubes. There are some 230,000 compounds in all. Somewhere in this giant haystack of molecules, there might be one or more "lead" molecules for new HIV protease inhibitors. A "lead" molecule is one that is similar to a final drug, but must first be modified by medicinal chemists to make it less toxic or more soluble in water. The NCI constructed a subset of this database that is supposed to represent the chemical variety of all the molecules in the complete database. This subset consists of nearly 2,000 chemical compounds and is called the "Diversity Set".
All life and viruses have a genetic blueprint, or "genome," that consists of a string of DNA letters. In the DNA alphabet, there are only 4 letters, or "bases" as they are known: A, C, G and T. These letters, when written in a particular order create "genes," genetic instructions on how to build "proteins," the molecular machines of life. The genome of the Human Immunodeficiency Virus (HIV) consists of nearly 10,000 bases, which code for just 9 genes. The most commonly-occurring form of HIV is known as the "wild type" form. When HIV infects its target cells, one of its proteins that it uses to replicate its own genetic instructions makes mistakes, and this gives rise to many "mutant" forms of HIV. Some of these mutants happen to be more resistant to the drugs currently used to treat HIV disease. So it is vital that we discover new drugs that are more robust, that can defeat not just the wild type but also the drug-resistant mutant forms of HIV.
One of the 9 genes in the HIV genome codes for a protein called "HIV protease." A protease is a molecular machine that cuts proteins. When HIV replicates, it converts its genetic instructions into one long chain of proteins, but for the virus to mature properly, it must cut the long "polyprotein" into separate proteins. If we block the active site of the protease with a small molecule, a bit like a key fitting into a lock, we can stop the virus from cutting the polyprotein, and thus prevent the virus from maturing into an infectious virus. This is exactly how clinically approved protease inhibitors work.
Stage 1a involved virtual screening of the 2,000 or so compounds in the NCI Diversity Set against 270 wild type and mutant HIV proteases to discover potential new leads and ultimately new drugs. We have analyzed the results for the wild type and have confirmed that our "positive controls" (molecules that we know bind to HIV protease) do, in fact, bind the most tightly to the wild type form of HIV protease, which verifies that the virtual screening is working. These include clinically-approved HIV protease inhibitors such as Indinavir, Saquinavir and Ritonavir, which are currently prescribed to HIV-infected patients. We have ranked the results from our virtual screening and will be presenting the best anti-HIV protease compounds from the NCI Diversity Set to our synthetic chemists so they can incorporate these "lead" molecules into the design of even better inhibitors than the clinically-approved drugs.
The next step is Stage 1b, where we will be screening 230,000 compounds -- the entire NCI database -- against just wild type HIV protease. This will allow us to validate not only the results of Stage 1a, but also the methodology of screening a diverse subset of a larger database against a target. We may discover new compounds against HIV protease, which we could not have found using just the Diversity Set.
We also are preparing Stage 2, which will involve screening virtual libraries of compounds designed in conjunction with our collaborating synthetic chemists against the broad panel of 270 wild type and mutant HIV proteases, again to find new protease inhibitors that work against more than just the most common form of HIV protease. Additionally, the top hits from Stage 1b will be investigated in more detail against this broad panel of 270 targets.
We are very pleased with the insight that we have gained thus far, which could not have been accomplished in the absence of World Community Grid. Thanks to the more than 170,000 volunteers donating their computing time, we have been able to do more than 2 quadrillion calculations, many of which are far more advanced than we have been able to do previously."
World Community Grid完成 FightAIDS@Home 的第一阶段
作者：Prof. Arthur J. Olson、Ph.D. Dr. Garrett M. Morris、M.A. (Oxon.)、D.Phil. (Oxon)、Dr. William M. Lindstrom、Jr., Ph.D., 和 Alexandre Gillet，Scripps 研究所
World Community Grid已经完成了FightAIDS@Home的一个重要的里程碑，完成于2005 年11月开始的FightAIDS@Home项目的Stage 1a。
国家癌症协会 (NCI) 有一个化学分子数据库，其中多数可以作为样本在试管中进行测试。里面总共约有 230,000个化合物。在这个庞大的分子库中，很可能有一个或多个的“有效”分子可以作为新的爱滋病毒蛋白抑制剂。“有效”分子是一种与最后的成品药物类似的一种蛋白质分子，但是必须首先被医学化学家修改，以减弱它的毒性或增强与水的溶解能力。NCI 先取出了数据库的一部分代表分子，以研究数据库中的分子的化学多样性。 这个子库有将近 2,000个化合物，我们叫他“对比库”。
所有的生物和病毒都有一个遗传基因的蓝图称为“基因组”，有一连串的 DNA 信息。在 DNA 类型表中，只有 4种“碱基”即: A 、 C 、 G 和 T。这些信息，以一个特定的次序组合即可产生“基因”－－它控制该如何生成生命的基本组成物质“蛋白质”。爱滋病毒 (HIV) 的基因组有将近 10,000个碱基，仅代表 9个基因编码。最常见的爱滋病毒的形式是“野生型”。当爱滋病毒感染到目标细胞的时候，它使用它的蛋白质复制自身的遗传基因，如果出错，就会产生许多“突变型”爱滋病毒。一些突变型病毒碰巧对现在使用的治疗爱滋病毒药物产生了更强的抗药性。因此我们寻找更有效的新药物是很重要的，他们不仅能抗击野生型，也能抗击突变型艾滋病毒。
在爱滋病毒基因组编码中的这 9个蛋白质基因中的一个被称为“爱滋病毒蛋白酶”。蛋白酶是一种切割蛋白质的分子机器。当爱滋病毒复制的时候，它把它的遗传基因信息转换成长的蛋白质链, 等病毒蛋白成熟后，它会把长的“聚合蛋白”切开。如果我们用一个小的分子绑在蛋白酶的活跃位置上，就象把钥匙插入一个锁内，我们就能阻止病毒切开聚合蛋白，这样一来就可以阻止病毒成熟转变成有传染性的病毒。这已经得到临床蛋白抑制剂研究的验明。
Stage 1a要把NCI“对比库”中的 2,000 个左右的化合物针对 270个野生型和突变型爱滋病毒蛋白进行虚拟筛选，以寻找潜在的新的有效和最终的药物。我们已经对野生型的结果进行了分析，而且已经确认我们的“积极控制”的做法，事实上，与野生型爱滋病毒蛋白酶绑得很紧，证实虚拟筛选是可行的。这些已由临床案例证实爱滋病毒蛋白抑制剂，比如 Indinavir 、 Saquinavir 和 Ritonavir，现在已用于爱滋病毒感染者的治疗。我们已经对来自我们的虚拟筛选的结果进行了排序，而且将从 NCI “多样性库”中选出最好的艾滋病病毒蛋白酶抑制分子送到我们的人造蛋白化学家那里，他们就造出比临床现在使用的药物更好的抑制剂。
再下一个步是Stage 1b，我们将会筛选 230,000个化合物-- 整个的 NCI 数据库 -- 针对野生型爱滋病毒蛋白酶。这不仅能让我们验证Stage 1a结果的有效性，也可以验证通过只计算一个目标的较大数据库的一个子集来检查整个数据库的方法学。我们可能发现“对比库”中没有的抗爱滋病毒蛋白的新化合物。
我们也正在准备阶段 2，将会增加与我们合作的人造蛋白化学家作出的分子，针对 270个野生型和突变型爱滋病毒蛋白酶进行虚拟筛选，寻找更多的爱滋病毒蛋白酶的新蛋白抑制剂（而不仅限于野生型蛋白酶）。此外，来自阶段 1b 的最好结果将会针对这270个目标进行更详细的测试。
我们对我们迄今已经得到的结果感到非常高兴，没有World Community Grid我们是没法完成的。感谢 170,000多个志愿者捐赠他们的计算机的计算时间，我们已经完成了超过 2000 的五次方的计算, 比我们以前完成的计算还要多很多。
[ Last edited by vmzy on 2006-5-19 at 17:51 ] |
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发表于 2005-11-20 18:11:51
发表于 2006-1-24 15:04:43