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

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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.