DNA-Encoded Chemistry Technology (DEC-Tec) Core

项目摘要-DNA编码化学技术(DEC-Tec)核心 DNA编码化学技术(DEC-Tec)核心的总体目标是使用DNA编码 经济高效地识别特定类药物探针和临床前候选药物的小分子文库 以生殖道特异蛋白质为靶点以达到避孕效果，并使我们的学术 生物学家将他们的基础科学转化为下一代非激素避孕药 男人和女人。发现新的避孕药物来治疗人口猖獗的增长和 预防意外怀孕是我们这个时代最具挑战性的科学和医疗保健问题之一。 一个主要的障碍是开发新药的成本。药物发现的临床前阶段，这利用了 高通量筛选(HTS)技术和广泛的药物化学，通常需要4年和 每一次毒品活动的成本为2000万美元。这些成本在学术界是站不住脚的，在 许多治疗领域的工业。为了克服学术药物发现的这一障碍，NIH P01拨款 利用DNA编码的化学库，这是BCM提供的独特资源。12月-Tec有 作为配体发现的替代技术出现，解决了限制和经济 HTS的不足之处。Dec-Tec通过允许审问以前所未有的规模对化学空间进行采样 分子种类增加1,000倍(到目前为止，我们的DEC-Tec库中有10亿种化合物，而现在只有1种 最好的HTS集合中有数百万种化合物)，从而直接确定高亲和力配体 以及我们避孕目标的结构-活性关系。在这项P01拨款中，我们的DEC-Tec Core将 询问30亿个DNA编码的类药物分子的新集合，以识别 具有非常适合快速发展到临床前评估的物理化学特征。进一步 使用我们的X射线结晶学和药物代谢设施可以实现优化。我们的整体 假设DEC-Tec将使我们能够快速和经济有效地识别多种类似药物的分子， 是针对基本的生精特定蛋白和受精特定蛋白，从而产生一种 为男性和女性提供的各种独特的避孕药具。这三个项目将使用DEC-Tec核心 同样如此。DEC-TEC核心将促进项目科学家工作的“目标行动小组”的概念 与DEC-Tec领导层、遴选科学家、化学家和化学信息学工作人员并肩审查 每个测试的类药物分子的体外和体内研究结果。这些目标行动小组将负责 设计和起诉化合物发现活动，并通过 额外的优化和测试。DEC-Tec核心将为我们的P01科学家提供独特的成本- 有效的药物发现资源，生产非激素化学探针和临床前候选药物 这将积极改变避孕药的发现，并有助于遏制世界范围内的人口增长。

PROJECT SUMMARY - DNA-Encoded Chemistry Technology (DEC-Tec) Core The overall goals of the DNA-Encoded Chemistry Technology (DEC-Tec) Core are to use DNA-encoded small-molecule libraries to cost-effectively identify specific drug-like probes and preclinical candidates to target reproductive tract-specific proteins for a contraceptive effect, and to empower our academic biologists to translate their fundamental science into next generation non-hormonal contraceptives for men and women. The discovery of new contraceptive medicines to treat rampant population growth and prevent unplanned pregnancies is one of the most challenging scientific and healthcare problems of our time. A major roadblock is the cost to develop new medicines. The preclinical phase of drug discovery, which utilizes high-throughput screening (HTS) technologies and extensive medicinal chemistry, typically takes >4 years and cost >$20 million for each drug campaign. These costs are untenable in academia and unsustainable in industry for many therapeutic areas. To overcome this hurdle in academic drug discovery, this NIH P01 grant takes advantage of DNA-encoded chemical libraries, a unique resource available at BCM. DEC-Tec has emerged as an alternative technology for ligand discovery that addresses the limitations and economic shortcomings of HTS. DEC-Tec samples chemical space on an unprecedented scale by allowing interrogation of >1,000-fold more molecular species (1 billion compounds in our DEC-Tec libraries to date compared to 1 million compounds in the “best” HTS collections), resulting in the direct determination of high-affinity ligands and structure–activity relationships for our contraceptive targets. In this P01 grant, our DEC-Tec Core will interrogate novel collections of 3 billion DNA-encoded drug-like molecules to identify drug-like compounds that possess physiochemical characteristics well-suited for rapid progression to preclinical evaluation. Further optimization can be achieved using our X-ray Crystallography and Drug Metabolism facilities. Our overall hypothesis is that DEC-Tec will allow us to rapidly and cost-effectively identify multiple drug-like molecules that are directed at essential spermatogenic-specific and fertilization-specific proteins, and thereby to create an assortment of unique contraceptives for men and women. The three Projects will utilize the DEC-Tec Core equally. The DEC-Tec Core will promote the concept of “Target Action Teams” in which Project scientists work side-by-side with DEC-Tec leadership, selection scientists, chemists, and cheminformatics staff to review in vitro and in vivo findings for each drug-like molecule tested. These Target Action Teams will be accountable for designing and prosecuting the compound discovery campaign and progressing drug-like leads through additional optimization and testing. The DEC-Tec Core will provide our P01 scientists with a unique and cost- effective drug discovery resource to produce non-hormonal chemical probes and preclinical drug candidates that will positively transform the discovery of contraceptives and help to contain world-wide population growth.