抗癌药物设计者的福音
http://www.100md.com
2004年8月20日
生物谷报道 Emory大学的研究人员与三个国家实验室研究人员合作，共同解开了一种很有潜力的、能终止细胞分裂的抗癌药物的结构之谜。这一发现可能打开了开发更高效的癌症治疗药物的大门。
研究人员分析了两个药物家族——epothilones和taxanes，其中包括抗癌药物Taxol。这两类药物都能通过结合到微管蛋白上相同的一个位点上，从而中断癌症细胞的分裂。微管蛋白是微管的重要组分，而微管则是细胞骨架的重要组成，也是细胞分裂时帮助分离染色体的重要组成。Epothilines或taxanes与微管蛋白结合时，蛋白就失去了弹性并使微管不能再解开，从而中止细胞分裂。
研究组利用Lawrence Berkeley国家实验室的电子显微镜衍射信息建立了这种模型。这些信息使研究人员能发现与两种药物结合的原子位置上的差异，从而揭示他们的活性机制。“揭示并绘制这个模型系统的结构将有助于全世界的研究人员在创制新型癌症药物方面取得进展，”Emory的化学家Jim Snyder说。这些结果发表在8月6号的Science上。文章中还附有药物epohilone A与控制细胞分裂的一种关键蛋白相互作用的结合位点的三维原子解析度图象。
, 百拇医药
主要研究者Jim Nettles说，“这项研究是一项交叉学科的合作研究，网络了不同学科的专家，包括化学、生物学、物理学、药理学。这也是研究成功的关键。”他还表示，希望这个模型系统能成为进行遗传药理学分析的一个临床工具——为每个病人适配最适合的药物。
艾默里大学的科学家和三个国际实验室的研究人员已经制定出能阻止细胞分裂的癌症药物epothilone A的结构，此发现将有助于研发更具疗效的癌症疗法。JimSnyder说：“定出此系统的结构将能帮助全球的科学家研发新的化合物，以找出新的癌症药物。”
研究人员目前正针对包含使用中的癌症药物Taxol的epothilones和taxanes两种药物家族进行研究。两种药物都借由tubulin结合以抑制癌症细胞分裂。Tubulin为微管体的组成物，组成细胞骨骼系统，并在分裂时做为染色体的支架。当epothilones或taxanes与tubulin结合，此蛋白质即失去弹性，微管体无法组合而抑制细胞分裂。
, 百拇医药
艾默里的团队使用得自电子显微镜获得的散射资料建构模型。所得资料使得他们能观察两种药物其分子位置的差异，以了解其在细胞内的活性。Jim Nettles说，此研究结合了多重不同领域的研究人员；此模式也将作为药物基因学方面有用的临床工具，以提供患者最好的药物。
Good News For Anticancer Drug Designers
Promising Families of Drugs Combat the Spread of Tumors in Different Ways
Contact: Lynn Yarris, (510) 486-5375
BERKELEY, CA – Pharmaceutical companies seeking to design more effective cancer chemotherapy agents may have an easier road ahead than was previously believed. A team of researchers, led by a scientist with the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), has shown that two of the most promising anticancer drug families, the taxanes, which include Taxol™, and the epothilones, have their own unique and independent mechanisms for combating the spread of tumors. This revelation provides drug designers with a great deal more flexibility in synthesizing new and improved forms of each.
, 百拇医药
"What our findings have done is to give drug designers more options," says Kenneth Downing, a biophysicist with Berkeley Lab's Life Sciences Division, who was the principal investigator for this study. "Nature has provided more than one way for these anticancer drugs to take action, which should make the job of the chemists attempting to synthesize novel analogues of these drugs easier."
Working with Downing on this study were Huilin Li, now with DOE's Brookhaven National Laboratory; James Nettles, Ben Cornett, and James Snyder of Emory University; and Joseph Krahn of the National Institute of Environmental Health Sciences. The results of their research appear in the August 6, 2004, issue of the journal Science.
, 百拇医药
Downing and his collaborators made their determinations after producing the first-ever three-dimensional, atomic-scale images of the binding site where one of the epothilones interacts with a protein that is crucial to a number of vital cell functions, including mitosis (cell division). This protein, called tubulin, is the major constituent of microtubules, hollow cylinders that serve as a skeletal system for cells.
For a cell to divide, the microtubule skeleton must first disassemble, then reform into spindles across which duplicate sets of DNA material line up, and then disassemble once more and reform into skeletal systems for the two new cells. The flexibility of the tubulin protein, coupled with a number of cellular regulators, enables microtubules to shift through these various formations.
, 百拇医药
"By binding to tubulin, epothilone acts as a microtubule stabilizer," says Downing. "When an epothilone molecule binds to tubulin, the protein loses its flexibility and the microtubules can no longer disassemble. That means cell division stops."
Since cancer is the result of cell division run amok, it has long been recognized in the field of medical research that microtubule stabilizers could prove valuable as cancer chemotherapy agents.
, 百拇医药
Taxanes are also microtubule stabilizers that bind with tubulin. Already Taxol, a natural substance found only in the bark of the Pacific yew tree, has been shown in clinical practice to be an effective treatment for a number of cancers including ovarian, breast, and lung. However, Taxol has a number of unpleasant side effects on patients, and treatment for recurrent cancers is often unsucccessful.
Because taxanes and epothilones are both microtubule stabilizers, it has been believed that a tubulin binding site called a pharmacophore, common to both families and with a specific set of chemical characteristics, could be found. This would be the route through which safer and more effective artificial forms of the taxanes, epothilones, and other natural anticancer compounds could be synthesized.
, http://www.100md.com
Through a combination of electron crystallography, nuclear magnetic resonance (NMR) spectroscopy, and molecular modeling, Downing and his collaborators were able to create a high-resolution, 3-D structural model of the site where the epothilone EpoA binds with tubulin. Much of this data was collected by Huilin Li of BNL's Department of Biology, who describes the challenges posed by the research.
"Using electron crystallography, we obtained the high-resolution electron density map, and were clearly able to localize the drug inside the protein density," Li says. "However, because of the relatively small size of EpoA (200 daltons) compared to the tubulin protein upon which it binds (100,000 daltons) — and the flexible nature of the drug structure — we had a hard time nailing down an exact binding structure for the drug. That's where the computational chemists at Emory University stepped in. They used computer modeling to come up with a drug structure that fit the observed density map."
, 百拇医药
In an earlier study, Downing and another group of colleagues had produced a similar model of the tubulin binding site of Taxol. When the two models were compared, it was revealed that tubulin possesses what is called a "promiscuous binding pocket." This means that several different compounds are able to bind at the same site through different chemical mechanisms.
Explains Downing, "Whereas Taxol and EpoA bind in the same region of the protein, the idea of a common pharmacophore doesn't apply, because they bind in such different ways."
, http://www.100md.com
The fact that Taxol and EpoA bind in such different ways may explain the observation that mutations to tubulin that produce strong resistance to one of these anticancer drugs provide only limited resistance to the other.
Says Downing, "It also suggests that treatment with a different microtubule stabilizing drug may be effective in cases where cancer recurs due to a tubulin mutation that produces Taxol resistance."
Downing and his collaborators have collected similar data on compounds from other microtubule stabilizers that share the same tubulin binding site as the taxanes and epothilones, and are now putting together 3-D structural models of them. The expectation is that these compounds will also have their own unique mechanism for interacting with tubulin.
"Our ultimate goal is to identify all of the different mechanisms that nature uses to stabilize tubulin activity and block mitosis," Downing says. "Ideally, chemists will be able to use our data to develop improved anticancer drugs.", 百拇医药
研究人员分析了两个药物家族——epothilones和taxanes，其中包括抗癌药物Taxol。这两类药物都能通过结合到微管蛋白上相同的一个位点上，从而中断癌症细胞的分裂。微管蛋白是微管的重要组分，而微管则是细胞骨架的重要组成，也是细胞分裂时帮助分离染色体的重要组成。Epothilines或taxanes与微管蛋白结合时，蛋白就失去了弹性并使微管不能再解开，从而中止细胞分裂。
研究组利用Lawrence Berkeley国家实验室的电子显微镜衍射信息建立了这种模型。这些信息使研究人员能发现与两种药物结合的原子位置上的差异，从而揭示他们的活性机制。“揭示并绘制这个模型系统的结构将有助于全世界的研究人员在创制新型癌症药物方面取得进展，”Emory的化学家Jim Snyder说。这些结果发表在8月6号的Science上。文章中还附有药物epohilone A与控制细胞分裂的一种关键蛋白相互作用的结合位点的三维原子解析度图象。
, 百拇医药
主要研究者Jim Nettles说，“这项研究是一项交叉学科的合作研究，网络了不同学科的专家，包括化学、生物学、物理学、药理学。这也是研究成功的关键。”他还表示，希望这个模型系统能成为进行遗传药理学分析的一个临床工具——为每个病人适配最适合的药物。
艾默里大学的科学家和三个国际实验室的研究人员已经制定出能阻止细胞分裂的癌症药物epothilone A的结构，此发现将有助于研发更具疗效的癌症疗法。JimSnyder说：“定出此系统的结构将能帮助全球的科学家研发新的化合物，以找出新的癌症药物。”
研究人员目前正针对包含使用中的癌症药物Taxol的epothilones和taxanes两种药物家族进行研究。两种药物都借由tubulin结合以抑制癌症细胞分裂。Tubulin为微管体的组成物，组成细胞骨骼系统，并在分裂时做为染色体的支架。当epothilones或taxanes与tubulin结合，此蛋白质即失去弹性，微管体无法组合而抑制细胞分裂。
, 百拇医药
艾默里的团队使用得自电子显微镜获得的散射资料建构模型。所得资料使得他们能观察两种药物其分子位置的差异，以了解其在细胞内的活性。Jim Nettles说，此研究结合了多重不同领域的研究人员；此模式也将作为药物基因学方面有用的临床工具，以提供患者最好的药物。
Good News For Anticancer Drug Designers
Promising Families of Drugs Combat the Spread of Tumors in Different Ways
Contact: Lynn Yarris, (510) 486-5375
BERKELEY, CA – Pharmaceutical companies seeking to design more effective cancer chemotherapy agents may have an easier road ahead than was previously believed. A team of researchers, led by a scientist with the U.S. Department of Energy's Lawrence Berkeley National Laboratory (Berkeley Lab), has shown that two of the most promising anticancer drug families, the taxanes, which include Taxol™, and the epothilones, have their own unique and independent mechanisms for combating the spread of tumors. This revelation provides drug designers with a great deal more flexibility in synthesizing new and improved forms of each.
, 百拇医药
"What our findings have done is to give drug designers more options," says Kenneth Downing, a biophysicist with Berkeley Lab's Life Sciences Division, who was the principal investigator for this study. "Nature has provided more than one way for these anticancer drugs to take action, which should make the job of the chemists attempting to synthesize novel analogues of these drugs easier."
Working with Downing on this study were Huilin Li, now with DOE's Brookhaven National Laboratory; James Nettles, Ben Cornett, and James Snyder of Emory University; and Joseph Krahn of the National Institute of Environmental Health Sciences. The results of their research appear in the August 6, 2004, issue of the journal Science.
, 百拇医药
Downing and his collaborators made their determinations after producing the first-ever three-dimensional, atomic-scale images of the binding site where one of the epothilones interacts with a protein that is crucial to a number of vital cell functions, including mitosis (cell division). This protein, called tubulin, is the major constituent of microtubules, hollow cylinders that serve as a skeletal system for cells.
For a cell to divide, the microtubule skeleton must first disassemble, then reform into spindles across which duplicate sets of DNA material line up, and then disassemble once more and reform into skeletal systems for the two new cells. The flexibility of the tubulin protein, coupled with a number of cellular regulators, enables microtubules to shift through these various formations.
, 百拇医药
"By binding to tubulin, epothilone acts as a microtubule stabilizer," says Downing. "When an epothilone molecule binds to tubulin, the protein loses its flexibility and the microtubules can no longer disassemble. That means cell division stops."
Since cancer is the result of cell division run amok, it has long been recognized in the field of medical research that microtubule stabilizers could prove valuable as cancer chemotherapy agents.
, 百拇医药
Taxanes are also microtubule stabilizers that bind with tubulin. Already Taxol, a natural substance found only in the bark of the Pacific yew tree, has been shown in clinical practice to be an effective treatment for a number of cancers including ovarian, breast, and lung. However, Taxol has a number of unpleasant side effects on patients, and treatment for recurrent cancers is often unsucccessful.
Because taxanes and epothilones are both microtubule stabilizers, it has been believed that a tubulin binding site called a pharmacophore, common to both families and with a specific set of chemical characteristics, could be found. This would be the route through which safer and more effective artificial forms of the taxanes, epothilones, and other natural anticancer compounds could be synthesized.
, http://www.100md.com
Through a combination of electron crystallography, nuclear magnetic resonance (NMR) spectroscopy, and molecular modeling, Downing and his collaborators were able to create a high-resolution, 3-D structural model of the site where the epothilone EpoA binds with tubulin. Much of this data was collected by Huilin Li of BNL's Department of Biology, who describes the challenges posed by the research.
"Using electron crystallography, we obtained the high-resolution electron density map, and were clearly able to localize the drug inside the protein density," Li says. "However, because of the relatively small size of EpoA (200 daltons) compared to the tubulin protein upon which it binds (100,000 daltons) — and the flexible nature of the drug structure — we had a hard time nailing down an exact binding structure for the drug. That's where the computational chemists at Emory University stepped in. They used computer modeling to come up with a drug structure that fit the observed density map."
, 百拇医药
In an earlier study, Downing and another group of colleagues had produced a similar model of the tubulin binding site of Taxol. When the two models were compared, it was revealed that tubulin possesses what is called a "promiscuous binding pocket." This means that several different compounds are able to bind at the same site through different chemical mechanisms.
Explains Downing, "Whereas Taxol and EpoA bind in the same region of the protein, the idea of a common pharmacophore doesn't apply, because they bind in such different ways."
, http://www.100md.com
The fact that Taxol and EpoA bind in such different ways may explain the observation that mutations to tubulin that produce strong resistance to one of these anticancer drugs provide only limited resistance to the other.
Says Downing, "It also suggests that treatment with a different microtubule stabilizing drug may be effective in cases where cancer recurs due to a tubulin mutation that produces Taxol resistance."
Downing and his collaborators have collected similar data on compounds from other microtubule stabilizers that share the same tubulin binding site as the taxanes and epothilones, and are now putting together 3-D structural models of them. The expectation is that these compounds will also have their own unique mechanism for interacting with tubulin.
"Our ultimate goal is to identify all of the different mechanisms that nature uses to stabilize tubulin activity and block mitosis," Downing says. "Ideally, chemists will be able to use our data to develop improved anticancer drugs.", 百拇医药