Core - Drug, Discovery, Design and Synthesis

核心 - 药物、发现、设计和合成

• 批准号: 8152937
• 负责人: Gunda I. Georg
• 金额: $ 112.45万
• 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/8152937
• 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; 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; Peptide Elongation Factor 1; 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, DDS) 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 Hsp90J3, eukaryotic elongation factor 1 a (eEF1A), Na,K-ATPase a4, Doublesex and Mab-3 related transcription factor-1 (Dmrt1), 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 ¿mu¿g/ml. 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） a.目的： 非激素男性避孕药的发现和开发尚处于起步阶段。然而，关于男性生殖系统的基础生物学知识已经爆炸，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。避孕药物必须高效、可逆、口服生物可利用或适合阴道内应用，并且安全。 为了应对这一机遇和挑战，我们已经组建了一个核心设施（药物发现，设计和合成核心，DDS），将支持这个跨学科的U54中心的专业知识，发现，设计，合成和开发男性避孕药。在与该中心的PI，其药物开发核心和NICHD的高度合作方式中，我们将优化命中和先导化合物的效力，选择性和药物特性，为临床试验做准备。 该中心的长期目标是开发非激素男性避孕药。对于目前的应用，我们已经选择了几个药物发现的目标，是重要的精子发生，精子，运动和获能。靶点是分子伴侣Hsp90J3、真核细胞延伸因子1a（eEF1A）、Na，K-ATP酶a4、Doublemex和Mab-3相关转录因子-1（Dmrt 1）和精子蛋白酪氨酸激酶。此外，预计U54中心未来的初级研究人员将研究其他靶蛋白。核心的中心研究假设是，可以在体外和体内发现、优化和研究每个靶标的小分子抑制剂，最终目标是将一种或多种药物推向临床试验。 研究人员为开展该项目做好了充分的准备，因为他们在生殖生物学、药物发现、药物开发方面有着良好的研究记录，并且在男性避孕药的发现和开发方面有着成功的合作历史。药物发现的研究环境也很好，并提供了在大学中不常见的独特设施，如高通量筛选实验室（KU），组合化学实验室（UMN），大规模合成实验室（UMN），治疗药物发现和开发办公室（KU）和常见的良好生产程序（c-GMP）合成设施（UMN）。 目的1：通过高通量筛选和靶向文库筛选筛选精子特异性靶点抑制剂。与项目PI合作，我们将开发适用于高通量筛选的检测方法。将筛选超过100，000种化合物的化合物文库和/或较小的靶向文库，以鉴定靶蛋白的小分子抑制剂。 目的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，蛋白质-命中复合物的结构将以原子分辨率确定。结构数据将用于基于结构的药物设计，以优化命中化合物的效力和选择性，并用于计算机筛选。 目标3：优化效价和选择性的筛选命中。小分子将优化的效力和选择性，使用基于结构的药物设计和其他合理的设计药物化学原则。 这些研究将与项目PI和药物开发核心密切合作进行。化合物将被制备、测试，然后进一步优化，目标是产生单位数纳摩尔抑制剂，其具有约1000倍的选择性和> 100 μ g/ml的水溶性。 目标4：开发用于临床前和临床评价的先导化合物。与药物开发中心和NICHD合作，我们将优化先导化合物的药物特性，为临床试验做准备。我们还将为动物研究提供大量的先导化合物。 我们对非激素男性避孕药的发现和开发的方法是创新的，因为我们已经确定了几个非常有前途的目标，以前没有探索药物发现。我们正在为这些项目带来最先进的药物发现方法，并期待与其他U54中心合作，为他们提供药物发现和开发资源以及学术机构很少提供的专业知识。 在为期五年的中心资助结束时，我们将为每个靶点确定小分子抑制剂，我们将与靶蛋白共结晶小分子抑制剂，并将使用有关蛋白质-抑制剂相互作用的结构信息进行药物设计。筛选命中将针对效力、选择性和药物特性进行优化，我们预计至少有一种优化的先导化合物将被选择用于临床试验，并最终商业化用于男性避孕。