标题: 分子间药理作用介面家族应用在磷酸化酵素-药物-疾病网络与机制之研究
Molecular Pharma-interface Families for Kinase-drug-disease Network and Mechanisms
作者: 杨进木
Yang, Jinn-Moon
国立交通大学生物科技研究所
关键字: 分子间药理作用介面家族;旧药新用;多标的药物;磷酸化酵素;癌症治疗;副作用;molecular pharma-interface family;new uses for old drugs;multi-target drugs;kinase;cancer treatment;side effect
公开日期: 2011
摘要: 目前的药物开发流程因其成本昂贵且需时极长,已逐渐不能满足市场对新药物的需求和应付紧急疫情。再者,过去的“单一药物针对单一标的,治疗单一疾病”的思维,在治疗病理现象复杂的疾病(如癌症)上也已经遇上瓶颈。在这样的情况下,“旧药新用”因为成本较低,而且可以迅速进入第二期临床实验观察其效果,因此成为愈来愈重要的议题。在本计划中,我们提出一个新概念“分子间药理作用介面家族(molecular pharma-interface family)”,以及新方法“作用位置分割地图(site-moiety map, SiMMap)”,希望达成三项目的:为若干种上市药物(包括中草药)找出新用途、开发多标的(multi-target)药物,并且建立一个针对国人常见癌症的磷酸化酵素-药物-疾病关联性网络资料库。

现在全球以分子立体结构为基础的药物设计工具通常难以找出蛋白质-配体结合介面上控制其生物功能的关键性位置(例如药效基团位置),针对这个问题,本研究团队在过去已发展出一套高准确率的分子嵌合工具GEMDOCK,迄今累积了近十年的一系列研究,是国内少数有能力自行研发药物设计技术的团队;我们也积极与国内外实验室合作,已先后为几个重要病原体找出抑制剂(≤10 μM),如登革病毒、流感病毒、胃幽门螺旋菌等等,且经过实验证实有抑制效果。GEMDOCK 亦曾于2007 年荣获国家新创奖。

目前我们已提出一套药效基团分析技术(即SiMMap),可以将蛋白质-配体结合介面依其立体形状及药效基团之性质做分群,形成“分子间药理作用介面家族”,属于同一家族的蛋白质也会与同一小分子化合物结合。换言之,这一群蛋白质共有一块由若干物化性质相似、空间位向相近的胺基酸片段组成的空间区域。SiMMap 能定位出这些药效作用区域,进一步为上市药找出未知的标的蛋白质(target protein),或用于开发新药、及评估药物副作用。

在本计划中,本团队将利用过去在系统生物学上累积的研究优势(包括已发表的“局部结构搜寻技术”等),与GEMDOCK 和SiMMap 结合,针对旧药新用、开发新药及建立国人常见癌症的磷酸化酵素-药物-疾病关联性网络资料库三项重要议题进行研究。我们是全球第一个提出“分子间药理作用介面家族”概念的团队,而我们的计算结果将与生物实验室合作,加以验证。当我们将这套观念运用在分析国内社会常见癌症如肺癌、肝癌、肠癌、胰脏癌时,我们的初步成果显示, 上市药物imatinib 除了能抑制KIT 和ABL1 磷酸化酵素而达到治疗胃肠道基质瘤(gastrointestinal stromal tumor)和慢性骨髓细胞白血病(chronic myeloid leukemia)的效果之外,MAPK8(肠癌、胰脏癌)、MAPK10(肠癌、胰脏癌)、KDR(血管增生,与肝癌及非小细胞肺癌有关)也具有可与KIT 及ABL1 归属于同一药理作用介面家族的配体结合位置,换言之,imatinib 也可能抑制MAPK8、MAPK10 及KDR;这一点在比对前人发表的实验论文后得到了证实。换句话说,这是研究旧药新用的一个良好起点。我们相信当这套技术与研究成果成熟,将对疾病治疗、降低药物副作用及药物成本,以及增进国民健康有所贡献。
The current costly and time-consuming framework of drug development is often unable to afford the requirements for new market drugs and emerging diseases. In addition, the 'one drug for one target for one disease' drug-discovery strategy cannot fully solve complex diseases, such as cancer and diabetes. Therefore, to discover a new drug from old drugs is a promising approach since old drugs are often approved by regulatory agencies for human and the new uses can be fast evaluated in phase II clinical trial. Here, we will propose a novel concept "molecular pharma-interface family" and Site-Moiety Map
(SiMMap) for finding new uses (or side effects) for old drugs (or Chinese herbs), discovering multi-target drugs, and developing a kinase-drug-cancer (disease) network database.

As protein structures increase rapidly, structure-based drug design and virtual screening approaches are becoming important and helpful in drug discovery. However, the major weakness of virtual screenings is likely due to incomplete understandings of ligand binding mechanisms and the subsequently imprecise scoring algorithms. These approaches generally cannot identify the key binding environments (e.g., pharmacophore spots) on protein-ligand interfaces that are essential to trigger or block the biological responses of the target protein. To address these issues, we have developed a molecular docking toolkit, namely GEMDOCK, which is one of wide-used tools in the world. We have cooperated with over 10 web laboratories for identifying lead compounds (such as dengue virus envelop protein, influenza virus neuraminidase, and anti-cancer inhibitors) and protein mechanisms (such as cAMP Receptor-Like Protein CLP and milk beta-lactoglobulin). Due to the achievement of GEMDOCK, we got
the 2007 National Innovation Award.

Recently, we have reported a structure-based pharmacophore (SiMMap) to show that members of molecular pharma-interface family often share a homologous fold and conserved structural features for interaction with chemically similar ligands throughout evolution. For example, protein kinases and isozymes that catalyze the same chemical reactions with different molecular structures or sequences are similar in binding environments; that is, these proteins are often share a set of space-related segments with similar physico-chemical properties and geometric shapes. The SiMMap can establish core binding
environments, which comprise both conserved binding sub-sites among proteins of molecular pharmainterface family and compound moieties, to discover the inhibitors of these proteins.

In this project, we will apply structural systems biology and Space-Related Pharmamotif (derived form our published method, 3D-BLAST) to enhance GEMDOCK and SiMMap for developing kinasedrug-disease network databases, discovering new kinase inhibitors for cancers, and identifying new uses for old drugs (potent lead compounds) and Chinese herbs. Protein kinases have a fundamental role in signal transduction pathways and play important roles in many cancers, such as non-small cell lung cancer (NSCLC), colorectal cancer, gastrointestinal stromal tumor (GIST), and leukemia. To our best knowledge, our approaches and databases are the first to acquire pharmacophore models (site-moiety map) and networks for understating biological mechanisms and identifying multi-target inhibitors based on molecular pharma-interface family. These computational results will be evaluated by bioassays. Our preliminary results show that the drug imatinib can inhibit kinases KIT and ABL1 for GIST and chronic myeloid leukemia; kinases MAPK10 and MAPK8 for colorectal and pancreatic cancers; and kinase insert domain receptor (KDR) for some solid tumors (e.g., hepatocellular carcinoma and NSCLC). We believe that the kinase-drug-disease network and molecular pharma-interface family are useful for new uses for old drugs and multi-target drugs. In addition, our results will make a great impact on public health.
官方说明文件#: NHRI-EX100-10009PI
URI: http://hdl.handle.net/11536/99603
https://www.grb.gov.tw/search/planDetail?id=2236224&docId=357460
显示于类别:Research Plans


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