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.

项目概要 爱达荷大学 INBRE 计划的行政补充建立了 INBRE-COBRE 研究合作。 INBRE 发展研究项目研究员 D. Xu 和 COBRE 项目 研究员 B. Morrison 将在一个名为“计算机辅助药物”的项目中结合他们的才能和专业知识 开发与过敏反应生物学相结合，以确定新的治疗方法。该项目汇聚了 徐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，用于研究过敏性高反应性 疗法。此次合作将提高双方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。过敏性高反应是一种常见的 导致生活质量下降和死亡率增加的令人衰弱的健康问题。主要例子 包括影响美国约 2600 万人的哮喘和影响美国超过 1800 万人的特应性皮炎 美国研究人员将重点放在 IL-13RA1 上，这是一种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。强有力的初步数据支持 该项目。使用两个 INBRE 数据科学核心设施，一个 NIH 化合物的高功率硅屏 文库结合细胞培养验证，他们发现了 40 种潜在的候选药物，可抑制 IL- 13RA1/IL-4R 复合物。在这些候选物中，他们确定了一种“主要”化合物：烟酰胺次黄嘌呤 二核苷酸，称为药物 4。他们的目标首先是使用 2D 扩展“命中先导”搜索 分子指纹和 3D 药效团可针对药物 4 筛选约 100 万种化合物。已鉴定 化合物将使用 3D 可视化驱动的配体设计、基于自由能的定量进行优化 构效关系（QSAR），以及计算吸收、处置、代谢、排泄和 毒性（ADMET）分析。其次，将确定药物 4 对人 IL-13RA1/IL-4R 信号传导的特异性 在细胞培养中。将使用慢病毒 shRNA 敲低方法在人类 A549 中测试受体信号传导 肺癌细胞。如果被破坏，配体结合的抑制将在小鼠细胞系 3T3-L1 中得到证实 表达并响应 IL-13 和 IL-4。该策略将适用于所有候选药物 确定。徐-莫里森的合作拥有强大的机构支持，并将使用 lDeA 构建的研究核心 实验室。该项目将使用两个 INBRE 发起的研究核心，即生物分子研究 博伊西州立大学中心和爱达荷州立大学分子研究核心设施。