CORE--Drug, Discovery, Design and Synthesis

核心——药物、发现、设计和合成

• 批准号: 8066373
• 负责人: Gunda I. Georg
• 金额: $ 44.28万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8066373
• 关键词: Animals; Arts; Bioavailable; Biological; Biological Assay; Biology; Clinical; Clinical Trials; Collaborations; Common Good; Complex; Computer Simulation; Contraceptive Agents; Core Facility; Data; Development; Digit structure; Drug Design; Elongation Factor; Environment; Future; Goals; Grant; Hormonal; In Vitro; Institution; Knowledge; Laboratories; Lead; Libraries; Male Contraceptions; Male Contraceptive Agents; Male Genital Organs; Methods; Molecular Chaperones; Na(+)-K(+)-Exchanging ATPase; National Institute of Child Health and Human Development; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Preparation; Procedures; Program Development; Property; Protein Tyrosine Kinase; Proteins; Recording of previous events; Reproductive Biology; Research; Research Personnel; Resolution; Resource Development; Screening procedure; Solubility; Spermatogenesis; Structure; Testing; Therapeutic; Universities; Ursidae Family; Vagina; Work; X-Ray Crystallography; aqueous; base; cell motility; combinatorial chemistry; design; drug development; drug discovery; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; high throughput screening; in vivo; infancy; inhibitor/antagonist; innovation; insight; pre-clinical; protein structure; research clinical testing; response; small molecule; sperm cell; sperm protein; transcription factor

3. Core Unit B: Drug Discovery, Design & Synthesis (Georg) a. Objective: The discovery and development of non-hormonal male contraceptive agents is in its infancy. However, knowledge about the basic biology of the male reproductive system has exploded and extensive biological insights provide the opportunity to initiate drug discovery and development programs. Contraceptive drugs must be highly effective, reversible, orally bioavailable or suitable for intra-vaginal application, and safe. In response to this opportunity and challenge we have assembled a core facility (Drug Discovery, Design & Synthesis Core, DOS) that will support this interdisciplinary U54 center with the expertise to discover, design, synthesize, and develop male contraceptive agents. In a highly collaborative manner with the Pis of this center, its drug development core, and the NICHD we will optimize hit and lead compounds for potency, selectivity, and pharmaceutical properties in preparation for clinical trails. The long-term goal of this center is the development of non-hormonal male contraceptive agents. For the current application we have selected several targets for drug discovery that are important for spermatogenesis, spermiation, motility and capacitation. The targets are the molecular chaperone Hsp90p, eukaryotic elongation factor 1oc (eEF1A), Na,K-ATPase a4, Doublesex and Mab-3 related transcription factor-1 (Dmrtl), and sperm protein tyrosine kinases. In addition, it is anticipated that future junior investigators of the U54-center will work on other target proteins. The central research hypothesis for the core is that small molecule inhibitors of each of the targets can be discovered, optimized, and investigated in vitro and in vivo with the ultimate goal to bring one or more agents towards clinical trials. The investigators are well prepared to undertake this project because they have a track record of research in reproductive biology, drug discovery, drug development, and a successful history of collaborating on the discovery and development of male contraceptive agents. The research environment for drug discovery is also excellent and provides unique facilities that are not often found at universities such as high throughput screening laboratories (KU), a combinatorial chemistry laboratory (UMN), a large-scale synthesis laboratory (UMN), an Office for Therapeutics Discovery and Development (KU), and a common Good Manufacturing Procedures (c-GMP) synthesis facility (UMN). Objective 1 : Identify inhibitors for sperm-specific targets by high throughput screening and by screening of targeted libraries. In collaboration with the project Pis, we will develop assays that are suitable for high throughput screening. A compound library of over 100,000 compounds and/or smaller targeted libraries will be screened to identify small molecule inhibitors of the target proteins. Objective 2: Determine protein-inhibitor interactions by protein X-ray crystallography. The target proteins will be co-crystallized with lead compounds and the structure of the protein-hit complex(es) will be determined at atomic resolution. The structural data will be used for structure-based drug design to optimize hit compounds for potency and selectivity and for in silico screening. Objective 3: Optimize screening hits for potency and selectivity. Small molecules will be optimized for potency and selectivity, using structure- based drug design and other rational design medicinal chemistry principles. These studies will be carried out in close collaboration with the project Pis and the Drug Development Core. Compounds will be prepared, tested and then further optimized with the goal to generate single digit nanomolar inhibitors that posses about 1000-fold selectivity and aqueous solubility of >100 Objective 4: Develop lead compounds for preclinical and clinical evaluation. In collaboration with the Drug Development Core and the NICHD we will optimize the pharmaceutical properties of lead compounds in preparation for clinical trails. We will also provide large-scale amounts of lead compounds for animal studies. Our approach toward the discovery and development of non-hormonal male contraceptive agents is innovative because we have identified several highly promising targets that have not been explored for drug discovery before. We are bringing state-of-the-art drug discovery methods to bear on these projects and are looking forward to working with the other U54 centers and providing them with drug discovery and development resources and expertise that are rarely available at academic institutions. At the end of the five-year center grant we will have identified small molecule inhibitors for each of the targets, we will have co-crystallized small molecule inhibitors with the target proteins and will have used structural information about protein-inhibitor interactions for drug design. The screening hits will have been optimized for potency, selectivity, and pharmaceutical properties and we expect that at least one optimized lead compound will have been selected for clinical trials and will ultimately be commercialized for male contraception.

3。核心单元B：药物发现，设计与合成（GEORG） 一个。客观的： 非激素男性避孕药的发现和发展仍处于起步阶段。然而， 关于男性生殖系统基本生物学的知识已经爆炸而广泛的生物学见解 提供了启动药物发现和开发计划的机会。必须使用避孕药 非常有效，可逆，口服生物利用或适合阴道内应用，并且安全。 为了应对这一机会和挑战，我们组建了一个核心设施（药物发现，设计和 合成核心，DOS），将支持这个跨学科的U54中心，并以发现，设计，设计， 合成并发展男性避孕剂。与该中心的PI高度协作， 它的药物发育核心以及NICHD，我们将优化效力，选择性，选择性的命中率和铅化合物 和药物特性为临床踪迹做准备。 该中心的长期目标是开发非激素男性避孕药。为了 当前的应用，我们选择了几个针对药物发现的靶标，对于精子发生很重要， 精子，运动和电容。目标是分子伴侣HSP90P，真核伸长 因子1OC（EEF1A），Na，K-ATPase A4，Doublesex和MAB-3相关转录因子1（DMRTL）和精子 蛋白酪氨酸激酶。此外，预计未来U54中心的初级调查员将有效 在其他靶蛋白上。核心的中心研究假设是每个分子的抑制剂 可以在体外和体内发现，优化和研究目标的最终目标 一个或多个临床试验的代理。 调查人员已经准备好进行该项目，因为他们有研究的记录 在生殖生物学，药物发现，药物开发以及在发现方面的成功历史 和男性避孕药的发展。药物发现的研究环境也是 优秀并提供独特的设施，这些设施在高通量筛查等大学中经常发现 实验室（KU），组合化学实验室（UMN），大规模合成实验室（UMN）， 治疗局发现与开发办公室（KU）和一个共同的良好制造程序 （C-GMP）合成设施（UMN）。 目标1：通过高吞吐量筛选和筛选确定精子特异性靶标的抑制剂 目标库。与PIS项目合作，我们将开发适合高的测定法 吞吐量筛选。一个超过100,000种化合物和/或较小目标库的化合物库是 筛选以鉴定靶蛋白的小分子抑制剂。 目标2：通过蛋白质X射线晶体学确定蛋白质抑制剂相互作用。靶蛋白 将与铅化合物共结晶，并将确定蛋白质冲击复合物（ES）的结构 在原子分辨率。结构数据将用于基于结构的药物设计以优化命中 具有效力和选择性的化合物以及用于硅筛的化合物。 目标3：优化筛选效果和选择性。小分子将用于优化效力 和选择性，使用基于结构的药物设计和其他合理设计药物化学原理。 这些研究将与PIS和药物开发密切合作进行 核。将准备，测试化合物，然后以生成单位数的目标进行进一步优化 纳摩尔抑制剂具有约1000倍的选择性和> 100的水溶性 目标4：开发用于临床前和临床评估的铅化合物。与 药物开发核心和NICHD我们将优化铅化合物的药物特性 准备临床踪迹。我们还将为动物研究提供大量铅化合物。 我们针对非激素男性避孕药的发现和发展的方法是创新的 因为我们已经确定了几个尚未探索药物发现的高度有希望的目标 前。我们正在带上最先进的药物发现方法来遵循这些项目，并正在寻找 转发与其他U54中心合作，并为他们提供药物发现和开发资源 和学术机构很少获得的专业知识。 在五年中心赠款结束时，我们将确定每个目标的小分子抑制剂， 我们将与靶蛋白共结晶的小分子抑制剂，并将使用结构 有关药物设计蛋白质抑制剂相互作用的信息。筛选将针对 效力，选择性和药物特性，我们希望至少一种优化的铅化合物 将被选为临床试验，并最终将商业化以进行男性避孕。