DRUG DISCOVERY CORE FACILITY

药物发现核心设施

• 批准号: 6198072
• 负责人: CHARLES D. SMITH
• 金额: $ 29.7万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198072
• 关键词: acyltransferase; antineoplastics; biomedical facility; chemical information system; chemical structure function; drug discovery /isolation; enzyme inhibitors; estrogen inhibitor; mitogen activated protein kinase; technology /technique development; transforming growth factors

Many academic researchers have excellent expertise in discovering proteins, ehzymes or genes that may be involved in cancer development or response to therapy. However, exploitation of these systems as targets for therapeutic drug development requires interests, experience and resources beyond those present in a typical research laboratory environment. This results in a lost opportunity for the researcher to demonstrate a role of the target in the disease state, as well as the loss of an opportunity to discover compounds with therapeutic potential. In a pharmaceutical company, such discovery would-most likely take place within a dedicated screening/chemistry division. This proposal seeks funding to establish a similar, albeit clearly more limited, core facility at Penn State University. The goal of this Drug Discovery Core Facility (DDCF) is to enable the development of faculty-identified proteins and/or genes as targets for anticancer drugs. This will proceed through the following interacting steps. The DDCF will closely collaborate with the Faculty Researcher to develop assays for inhibitors or activators of their protein of interest. The DDCF will maintain a collection of compounds to be tested in these assays, conduct the actual screening process and analyze data by molecular modeling for Quantitative Structure-Activity Relationships (QSARs). At this point, the Project Leader will have lead compounds and defined families of compounds upon which further study can be focused. For example, the lead compounds will provide useful new tools .for the pharmacological manipulation of the target and evaluation of biological consequences. Additionally, the QSAR information could then be used to direct the synthesis of new optimized compounds and/or the purchase of commercially available compounds. The recent availability of commercial screening libraries, equipment for medium-throughput screening, and software for ligand-based QSAR development has enabled this approach to drug discovery in an academic environment. The feasibility of this process has been validated by the experience of the Principal Investigator in developing novel antagonists of drug transport proteins. Establishment of this DDCF will provide an important bridge between basic and applied research, and so will enhance the research environment and advance cancer research.

许多学术研究人员在发现可能参与癌症发展或治疗反应的蛋白质、酶或基因方面拥有出色的专业知识。然而，利用这些系统作为治疗药物开发的目标需要超出典型研究实验室环境中存在的兴趣、经验和资源。这导致研究人员失去了证明靶标在疾病状​​态中的作用的机会，也失去了发现具有治疗潜力的化合物的机会。在制药公司中，此类发现很可能在专门的筛选/化学部门内进行。该提案寻求资金在宾夕法尼亚州立大学建立一个类似的、尽管明显更有限的核心设施。该药物发现​​核心设施 (DDCF) 的目标是开发教师鉴定的蛋白质和/或基因作为抗癌药物的靶标。这将通过以下交互步骤进行。 DDCF 将与学院研究员密切合作，开发其感兴趣蛋白质的抑制剂或激活剂的检测方法。 DDCF 将维护一系列要在这些测定中测试的化合物，进行实际的筛选过程，并通过定量构效关系 (QSAR) 的分子建模来分析数据。此时，项目负责人将拥有先导化合物和定义的化合物家族，以便进一步研究。例如，先导化合物将为靶标的药理学操作和生物学后果的评估提供有用的新工具。此外，QSAR 信息可用于指导新的优化化合物的合成和/或购买市售化合物。最近出现的商业筛选库、中等通量筛选设备和基于配体的 QSAR 开发软件使这种方法能够在学术环境中进行药物发现。首席研究员开发新型药物转运蛋白拮抗剂的经验已经验证了该过程的可行性。该DDCF的成立将为基础研究和应用研究之间架起一座重要桥梁，从而改善研究环境并推进癌症研究。