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

项目摘要 爱达荷州大学INBRE项目行政副刊建立了INBRE-COBRE 研究合作。INBRE-发展研究计划调查员，D.Xu，和Cobre-Project 研究人员B.莫里森将把他们的才华和专业知识结合在一个名为计算机辅助药物的项目上 与过敏反应生物学相结合的开发，以确定新的疗法。该项目汇集了 徐在计算机辅助药物开发方面的计算生物化学专业知识和莫里森的细胞和 细胞培养和免疫学研究过敏性高反应的分子生物学专业知识 治疗学。这一伙伴关系将提高两名调查人员的科学工作质量，并增加 为本科生和研究生提供研究机会。过敏性高反应是一种常见的 和衰弱的健康问题，导致生活质量下降和死亡率增加。最好的例子 包括哮喘，在美国影响到约2600万人，以及特应性皮炎，影响到美国的1800万人 美国调查人员正将重点放在IL-13RA1上，IL-13RA1是过敏反应中的关键受体 目前还没有有效的药物来阻断受体结合的负面影响。强劲的初步数据支持 这个项目。使用两个INBRE数据科学核心设施，NIH化合物的大功率硅屏 文库与细胞培养验证相结合，他们发现了40种潜在的候选药物，可以抑制IL-1 13RA1/IL-4R复合体。在这些候选化合物中，他们发现了一种“先导”化合物，烟酰胺次黄嘌呤 二核苷酸，被称为药物4。他们的目标将是，首先，使用2D来扩大“命中到领先”的搜索 分子指纹和3D药效团筛选~100万个抗药物化合物4.鉴定 化合物将使用3D可视化驱动的配体设计、基于自由能的定量设计进行优化 构效关系(QSAR)和计算吸收、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信号的特异性 在细胞培养中。将使用慢病毒shRNA敲除方法在人类A549中测试受体信号 肺癌细胞。如果被干扰，将在小鼠细胞系3T3-L1中证实配体结合的抑制 表达并对IL-13和IL-4做出反应。这一策略将适用于所有候选药物 已确认身份。徐和莫里森的合作有强大的制度支持，并将使用lDeA建立的研究核心 实验室。两个由INBRE发起的研究核心将用于这个项目--生物分子研究 博伊西州立大学分子研究中心和爱达荷州立大学分子研究核心设施。

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.