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发表于 2005-3-26 16:32:15
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这是2003年的新闻了，那个时候与D2OL相关的新闻特别的多，我也转几篇吧。不过这两年就少得基本上看不到了。
加入网格计算，找寻SARS解药——专访参与“非典”科研攻关的旅美华人科学家许田
http://www.d2ol.com/
d2ol网站地址
To all members of the D2OL community,
My name is Dr. Bonnie Gould Rothberg and I am the Medical Director of the Rothberg Institute, your D2OL host. On behalf of The Rothberg Institute, I would like to thank you for your time and efforts in helping us crunch towards a cure for SARS.
The strengths of a global community working in harmony have really been a driving force behind all areas of SARS research. The SARS epidemic was first brought to international attention in February and scientists from all over the world have been working at breakneck speeds towards getting at the heart of SARS. In fact, in less than 3 months, this international collaboration has led to the identification of the virus that causes SARS, the complete identification of its genetic code (i.e., its DNA sequence) and, most recently, identification of a key protein made by the SARS virus that, if shut down by a drug, could stop the SARS infection. The speed of this progress probably sets a new world record for scientific discovery. For those who wish to read the scientific literature on SARS, please visit www.nejm.org for the May 15th issue of the New England Journal Of Medicine and www.sciencemag.org for the genetic code of the SARS virus and the protein structure of this key target.
Amid this backdrop of breakneck discovery, you all have volunteered computer time to our D2OL effort against SARS. I would, then like to update you all of the progress on this project and inform you of the scientific strategy behind the SARS arm of D2OL.
1. Selection of a target for SARS
Since we posted our SARS target close to 4 weeks ago, folks have wanted to learn more about the target we selected and how interfering with this particular target will ultimately stop the SARS infection. A simple explanation follows.
The SARS virus is a member of the coronavirus, or crown-virus (under the microscope, they look like they wear crowns), family. And, to a large extent, all coronaviruses are related. So, while scientists are still learning about the intricacies of the SARS virus, there are 7 other coronaviruses that scientists are much more familiar with and have been, in fact, studying for over 30 years. Over the years, scientists have come to learn about many aspects of the coronavirus life cycle-facts that are common to all members of the coronavirus family. So, when we learned 4 weeks ago that the SARS virus was a coronavirus, even without having lots of knowledge about the specifics about the SARS virus we could apply basic ideas common to all coronaviruses to SARS. And that is what we did.
All coronaviruses make a protein called the "Coronavirus Main Protease" or 3CL-PRO , for short. This protein is absolutely essential for the virus to make copies of itself and spread the infection, so stopping this protein from working would very likely stop the virus. This protein is also very ~y from a drug development standpoint. Pharmaceutical companies already know how to make drugs that inhibit proteases made by viruses (e.g., ritonavir and indinavir are major components of anti-HIV drug regimens). It also turns out that the Agouron division of Pfizer has already successfully made drugs against the 3CL-PRO protein found in the virus responsible for the common cold (rhinovirus). The Coronavirus Main Proteinase is, therefore, an excellent drug target for anti-SARS therapy and why we selected this target 4 weeks ago.
2. Of Pigs and Man
As many of the techies already know, to prepare a drug target to work in a docking environment, it is essential that its X-ray crystal structure be solved. This work is typically done by expert biophysicists working in either industrial or academic labs. In order for D2OL to consider drug discovery against 3CL-PRO, we needed the coordinates for the protein as determined by X-ray crystal structure. Four weeks ago, (before the SARS virus was characterized) we were very fortunate to find that a group working in Germany had, a few years back, worked out the X-ray crystal structure for the 3CL-PRO from a coronavirus that causes diarrhea in pigs ( the transmissible gastroenteritis virus, TGEV ). Because we knew that all coronaviruses are very similar to each other, we made the basic assumption that since the 3CL-PRO was so essential for the coronavirus to work properly that the 3CL-PRO structure was likely to be very similar if not identical among all members of the coronavirus family. We had some evidence of this from the German group who, in their work from 2001, had shown that the key pieces of the 3CL-PRO protein were identical across all 7 of the coronaviruses they looked at. We thus uploaded to the community the 3CL-PRO identified from the pig coronavirus TGEV as a target that will help us find drugs against SARS. Just yesterday, the same German group that previously worked on the TGEV structure published in the journal Science (if you publish here, you are a star and you are made ) that they solved the structure for 3CL-PRO from a coronavirus that causes a variety of the human cold (a.k.a. HCo-V) and based on this structure and that from the TGEV, they were able to deduce the structure of the SARS coronavirus 3CL-PRO. Their conclusions were as follows:
1. As per our assumption, the guts of the 3CL-PRO (the parts that make it work correctly) are the similar enough across all coronaviruses such that drugs that are useful for one type should be useful for all
2. Based on the work done by the Agouron scientists, the German team concluded that 3CL-PRO would be an outstanding target to stop SARS.
But we all already knew this 4 weeks ago .
3. So what's next? .
First and foremost, at The Rothberg Institute, we are scientists. Now that we have spent our 5 minutes patting ourselves on the back for picking the right target in 3CL-PRO, we have been very carefully reading the Science paper from the German group and using it to help us put together an action plan. I would like to share that plan with you all.
A. Updating and adding more SARS targets. Now that the actual X-ray crystal structure for the 3CL-PRO from the HCo-V human coronavirus is known and the SARS version is strongly suggested, we will be adding these ASAP (should be up by the end of the month) as SARS targets II & III. By crunching all 3 flavors of the coronavirus 3CL-PRO, we should be able to identify candidate molecules that are ranked as top candidates for all 3 targets. We hope that the probability of getting a drug to score high for all 3 targets by chance alone is much less than if it is due to real chemical factors. Candidates making the tops of all 3 lists then have a better chance of owrking at the lab bench, thus speeding up our efforts.
B. Learning from Agouron/Pfizer. As I have mentioned, the scientists at Agouron have already worked extensively with the cold virus (rhinovirus) 3CL-PRO and have even made drugs that have tight binding to it. All of this has been published in the scientific literature. We would like to leverage their knowledge to help make our effort more tightly controlled. Firstly, we will also load up a 4th target, the 3CL-PRO from the rhinovirus-the same one that Agouron worked on. So don't be surprised when folks see this target as one to crunch. We are also going to load up all of the chemicals that Agouron has published that bind to the the rhinovirus 3CL-PRO and mix these up with the candidates that we already have. Then we will see if our computer can pull up the Agouron molecules as strong candidates for the rhinovirus 3CL-PRO (it should). If it does, we know for certain that our program is optimized to crunch for good targets for 3CL-PROs. If we get less than perfect results, our computational chemists on staff will be put to the task of tweaking D2OL to get a better fit between the Agouron drugs and the rhinovirus 3CL-PRO. For the non-scientists out there, this part of the experiment is called the "control" and is an essential part for any experiment. Good controls are what sets apart good science from hocus-pocus magic.
Please do look for the new changes to your D2OL client in the next few weeks. And, as always, we'll be posting updates when these changes are about to happen.
We will also be happy to respond to members of the community who may have additional questions.
Thanks,
Dr. Bonnie
加入网格计算，找寻SARS解药——专访参与“非典”科研攻关的旅美华人科学家许田
只要你是一位能上网的个人电脑用户，就有机会为早一天找到对抗非典型肺炎的特效药贡献一份力量，为人类在与“非典”病毒的赛跑中增加一份优势。你所需要付出的，只是电脑闲置不用的时间。
旅美华人科学家、耶鲁大学医学院遗传学助理教授许田参与领导的Ｄ２ＯＬ网格计算项目，最近将“非典”病毒列为运算目标之一，希望能集大量个人电脑之力形成一台虚拟的超级计算机，加速进行抗“非典”药物筛选。
希望参与这个项目的个人电脑用户，只需要到http://www.d2ol.com网站下载并安?... 话悴恍枰没Ц稍ぁ?/a>
网格计算是在个人电脑普及和互联网发展的基础上产生的一种新型运算方式，它通过网络联合众多个人电脑的力量，利用这些电脑的闲置运算能力来解决需要大量科学运算的问题。
Ｄ２ＯＬ网格计算项目由美国罗斯伯格儿童疾病研究所主持，该研究所是设在耶鲁附近的一家非营利科研机构，许田是研究所科学顾问委员会主席。他同时也是上海复旦大学的访问教授，在这次“非典”危机中主动请缨参加上海市的科研攻关。
许田在接受新华社记者电话采访时说，Ｄ２ＯＬ项目筛选出比较有希望成为抗“非典”药物的化学物质后，复旦大学的科学家将在实验室中将这些物质作用于“非典”病毒，观察实际效果。此外，运算结果还将立即在网上无偿公开，供全世界所有研究者共享。
Ｄ２ＯＬ项目于２００２年上半年启动，起初的运算目标是埃博拉病毒、炭疽热杆菌和天花病毒。由于最近几个月来“非典”在世界特别是中国肆虐，焦虑万分的许田和他的美国同事们决定将“非典”病毒加入运算目标之列，并作为目前的工作重点。自“非典”部分的运算４月１７日启动以来，截至５月１０日，参与Ｄ２ＯＬ项目的个人电脑已由原先的２．９万台增加到５．５万台。
许田说，以生物学为基础，通过互联网利用个人电脑的闲置时间来进行计算机筛药，是近几年才出现的一种研制药物的新方法。单独一台个人电脑的能力很微小，但许多台结合起来，就能形成非常强大的运算能力。他说，现在参与Ｄ２ＯＬ项目的５．５万台个人电脑，力量已经超过１０台最好的超级计算机。
传统的新药研制方法，是在实验室里直接将化学物质作用于病菌或毒等等病原体，或与病原体活性密切相关的蛋白质，观察哪些物质能抑制病原体生长。由于很难预期数以百万种计的化学物质中哪些可能有效，逐一试验的过程需要耗费大量人力物力。通常一种新药的研制需要十多年时间、几亿乃至十几亿美元。
分子生物学的发展，使人们能够预先在计算机上对化学物质进行筛选，挑选出少数比较有潜力的物质，然后在实验室中进行有针对性的试验。
许田说，病毒的活性与特定的蛋白质密切相关，如果一种化合物能与其中某一种蛋白质的活性中心紧密结合，使该活性中心不能再与人体细胞里本来的攻击目标结合，就可以使蛋白质失活，妨碍病毒生长。药物筛选，就是寻找能与目标蛋白质结合得最好的化学物质。
他说，打一个通俗的比喻，目标蛋白质好比是一把锁，拿一个与锁孔比较相配的东西塞进去把锁孔堵上，钥匙就不能再开锁，锁也就坏了。知道目标蛋白质的分子结构，也知道待选化学物质的分子结构，好比知道锁的结构和堵塞物的形状，可以用计算机先算一算哪种形状的堵塞物最有效，大大减少实际试验的范围。
这样的筛选工作运算量极为庞大，需要超级计算机才能完成，代价昂贵。而利用网络把许多普通的个人电脑连起来，利用其闲置能力进行运算，可以大大加快新药研制的速度。
许田说，现在Ｄ２ＯＬ项目已经算出了几种比较有希望的抗“非典” 物质。上海市正在加紧建设进一步研究需要的动物实验室，建成后，科学家将根据积累的运算结果在小鼠身上进行动物试验。
他说，现在还不能预期Ｄ２ＯＬ最终是否能帮人们找到对抗“非典” 的特效药，但既然疫情如此严重，就必须进行努力。他们希望对１００万种物质进行筛选。此外，目前的运算目标只是“非典”病毒众多蛋白质的一种蛋白酶，将来还有可能需要对其它蛋白质进行计算，因此需要尽可能多的个人电脑加入进来。
目前，互联网上最大的网格计算项目是分析射电望远镜数据、寻找地外智慧生命的ＳＥＴＩ＠ＨＯＭＥ计划，参与该计划的计算机已接近４５０万台。 |
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发表于 2005-3-26 16:02:59