DNA-Encoded Chemistry Technology (DEC-Tec) Core

DNA 编码化学技术 (DEC-Tec) 核心

基本信息

批准号：
10164825
负责人：
Damian Winston Young
金额：
$ 38.38万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10164825
关键词：
Academia Address Affinity Area Characteristics Chemicals Chemistry Clinic Collection Contraceptive Agents DNA Data Development Drug Kinetics Economics Fertility Fertilization Foundations Genes Genetic Genomic DNA Germ Cells Goals Grant Healthcare In Vitro Industry Informatics Knowledge Lead Leadership Libraries Ligands Medicine Molecular Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Phase Play Population Growth Preclinical Drug Development Program Research Project Grants Property Proteins Research Personnel Resources Role Sampling Science Scientist Series Side Spermatogenesis Structure Structure-Activity Relationship Technology Testing Therapeutic Time Toxic effect Translating United States National Institutes of Health Woman Work X-Ray Crystallography base cheminformatics contraceptive target cost cost effective design drug candidate drug discovery drug metabolism experience follow-up functional genomics high throughput screening improved in vivo innovation men metabolomics next generation novel pre-clinical preclinical evaluation prevent reproductive reproductive tract small molecule small molecule libraries structural biology unintended pregnancy

项目摘要

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.

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 编码小分子库，可经济有效地识别特定的类药探针和临床前候选药物以生殖道特异性蛋白质为靶点以达到避孕效果，并增强我们的学术能力生物学家将他们的基础科学转化为下一代非激素避孕药发现新的避孕药物来治疗人口的急剧增长和预防意外怀孕是当今时代最具挑战性的科学和医疗保健问题之一。一个主要障碍是开发新药的成本，该阶段利用药物发现。高通量筛选 (HTS) 技术和广泛的药物化学，通常需要 4 年以上的时间每次禁毒运动的成本超过 2000 万美元，这些成本在学术界是难以承受的，在学术界也是不可持续的。为了克服学术药物发现中的这一障碍，NIH P01 拨款。利用 DNA 编码的化学库，这是 BCM 提供的独特资源。作为配体发现的替代技术出现，解决了局限性和经济性 HTS 的缺点是通过允许审讯以前所未有的规模对化学空间进行采样。超过 1,000 倍的分子种类（迄今为止，我们的 DEC-Tec 库中有 10 亿种化合物，而 1 “最佳”HTS 集合中的百万种化合物），从而直接测定高亲和力配体我们的避孕目标的结构-活性关系在这项 P01 资助中，我们的 DEC-Tec 核心将。询问 30 亿个 DNA 编码的类药分子的新集合，以识别类药化合物具有非常适合快速进展到临床前评估的理化特征。使用我们的 X 射线晶体学和药物代谢设施可以实现优化。假设 DEC-Tec 将使我们能够快速且经济高效地识别多种药物样分子，针对必需的生精特异性和受精特异性蛋白质，从而创建这三个项目将利用 DEC-Tec Core 提供各种独特的男性和女性避孕药具。同样，DEC-Tec 核心将推广项目科学家工作的“目标行动团队”概念。与 DEC-Tec 领导层、选择科学家、化学家和化学信息学工作人员并肩进行审查这些目标行动小组将负责对每个测试的药物样分子进行体外和体内研究。设计和实施化合物发现活动并通过以下方式推进类药物先导化合物 DEC-Tec Core 将为我们的 P01 科学家提供独特且成本低廉的解决方案。有效的药物发现资源，用于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具的发现并有助于遏制世界人口增长。