Idaho INBRE Program- Computer-aided drug development coupled with allergic response biology to identify novel therapeutics

爱达荷州 INBRE 计划 - 计算机辅助药物开发与过敏反应生物学相结合，以确定新的治疗方法

• 批准号: 10766460
• 负责人: Carolyn Hovde Bohach
• 金额: $ 19.05万
• 依托单位: UNIVERSITY OF IDAHO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10766460
• 关键词: 3-Dimensional; A549; Address; Administrative Supplement; Affect; Allergic; Asthma; Atopic Dermatitis; Binding; Biochemistry; Bioinformatics; Biological; Biology; Biomedical Research; Cell Culture Techniques; Cellular biology; Centers of Research Excellence; Central Nervous System; Collaborations; Complex; Computer Assisted; Computer Simulation; Computing Methodologies; Core Facility; Coupled; Couples; Data; Data Science; Data Science Core; Development; Dinucleoside Phosphates; Effectiveness; Environment; Excretory function; Fostering; Free Energy; Funding; Future; Goals; Health; Human; Hypersensitivity; Hypoxanthines; IL13RA1 gene; Idaho; Immunology; Infrastructure; Institution; Interleukin-13; Interleukin-4; Intravenous infusion procedures; Investments; Laboratories; Lead; Learning; Libraries; Life; Ligand Binding; Ligands; Malignant Epithelial Cell; Metabolism; Modeling; Molecular; Molecular Biology; Molecular Profiling; Monoclonal Antibodies; Mouse Cell Line; Niacinamide; Outcome; Persons; Pharmaceutical Preparations; Quality of life; Quantitative Structure-Activity Relationship; Receptor Signaling; Research; Research Personnel; Scientist; Signal Transduction; Specificity; Structure; Students; Supporting Cell; System; Talents; Testing; Therapeutic; Tissues; Toxic effect; Training; United States National Institutes of Health; Universities; Validation; Work; absorption; allergic airway inflammation; allergic response; biomedical scientist; candidate identification; career; computer program; design; drug candidate; drug development; drug discovery; experience; graduate student; human disease; in silico; knock-down; lung Carcinoma; mortality; mouse model; novel; novel therapeutics; pharmacophore; programs; receptor; receptor binding; screening; small hairpin RNA; synergism; targeted treatment; three-dimensional visualization; tissue culture; undergraduate research experience; undergraduate student

Project Summary This Administrative Supplement to the University of Idaho INBRE Program establishes an INBRE-COBRE research collaboration. The INBRE-Developmental Research Program Investigator, D. Xu, and COBRE-project investigator, B. Morrison, will combine their talents and expertise on a project titled, Computer-aided drug development coupled with allergic response biology to identify novel therapeutics. The project brings together Xu’s computational biochemistry expertise in computer-aided drug development and Morrison’s cell and molecular biology expertise in cell culture and immunology to investigate allergic hyperresponsiveness therapeutics. The partnership will enhance the quality of scientific work for both investigators and increase research opportunities for undergraduate and graduate students. Allergic hyperresponsiveness is a common and debilitating health issue that results in a reduced quality of life and increased mortality. Prime examples include asthma, affecting ~26 million people in the U.S. and atopic dermatitis, affecting >18 million people in the U.S. The investigators are focusing their efforts on IL-13RA1, a key receptor in allergic responses for which there is no efficacious drug to block the negative effects of receptor binding. Strong preliminary data supports the project. Using two INBRE Data Science Core facilities, a high-power in silico screen of NIH compound libraries coupled with cell culture validation they found 40 potential drug candidates that inhibit the IL- 13RA1/IL-4R complex. Among these candidates they identified a ‘lead’ compound, nicotinamide hypoxanthine dinucleotide, referred to as Drug 4. Their goals will be to, first, expand the ‘hit-to-lead’ search using 2D molecular fingerprint and 3D pharmacophore to screen ~1 million compounds against Drug 4. Identified compounds will be optimized using 3D visualization driven ligand design, free energy-based quantitative structure-activity relationship (QSAR), and computational absorption, disposition, metabolism, excretion and toxicity (ADMET) analyses. Second, Drug 4 specificity for human IL-13RA1/IL-4R signaling will be determined in cell culture. Receptor signaling will be tested using a lentiviral shRNA knockdown approach in human A549 lung carcinoma cells. If disrupted, inhibition of ligand binding will be confirmed in the mouse cell line 3T3-L1 that expresses and responds to both IL-13 and IL-4. This strategy will be applied for all drug candidates identified. The Xu-Morrison collaboration has strong institutional support and will use lDeA-built research core laboratories. Two INBRE-initiated research cores will be used in this project, the Biomolecular Research Center at Boise State University and the Molecular Research Core Facility at Idaho State University.

项目摘要 爱达荷大学inbre计划的这种行政补充计划建立了一个近亲赛车 研究合作。 Inbre开发研究计划研究员D. XU和Cobre-Project 调查员B. Morrison将在一个名为“计算机辅助药物”的项目上结合其才能和专业知识 发育再加上过敏反应生物学，以鉴定新的疗法。该项目汇集了 Xu在计算机辅助药物开发方面的计算生物化学专业知识以及莫里森的细胞和 细胞培养和免疫学方面的分子生物学专业知识，以研究过敏性高反应性 治疗。伙伴关系将提高研究人员的科学工作质量并增加 本科生和研究生的研究机会。过敏性过敏是常见的 和使人衰弱的健康问题导致生活质量降低和死亡率增加。主要例子 包括哮喘，影响美国约2600万人和特应性皮炎，影响> 1800万人 美国调查人员将精力集中在IL-13RA1上，这是过敏反应的关键受体 没有有效的药物可以阻止受体结合的负面影响。强大的初步数据支持 使用两个Inbre Data Science核心设施，这是NIH化合物硅屏幕中的一个高功率 图书馆和细胞培养验证结合，他们发现40种潜在的候选药物抑制IL- 13RA1/IL-4R复合物。在这些候选人中，他们确定了“铅”化合物烟酰胺低黄嘌呤 Dinucleotide，称为药物4。他们的目标是首先使用2D扩展“命中率”搜索 分子指纹和3D药效团至筛选约100万种药物4的化合物。 化合物将使用3D可视化驱动配体设计，基于自由能的定量进行优化 结构活动关系（QSAR）以及计算滥用，处置，代谢，排泄和 毒性（ADMET）分析。其次，将确定人IL-13RA1/IL-4R信号的药物4特异性 在细胞培养中。受体信号将使用人A549中的慢病毒shRNA敲低进近测试受体信号传导 肺癌细胞。如果破坏，将在小鼠细胞系3T3-​​L1中确认配体结合的抑制作用 这表达并响应IL-13和IL-4。此策略将用于所有候选毒品 确定。 Xu-Morrison合作具有强大的机构支持，并将使用LDEA-BUNUILD研究核心 实验室。该项目将使用两个近亲发起的研究核心，即生物分子研究 博伊西州立大学和爱达荷州立大学的分子研究核心设施中心。