FGF23 is a bone derived hormone that plays an essential physiological role in regulating phosphate and vitamin D homeostasis through activation of FGF receptor/a-Klotho membrane complexes in target tissues. Increased circulating FGF23 underlie several hereditary hypophosphatemic diseases, whereas FGF23 loss-of-function leads to tumoral calcinosis syndromes. Elevated FGF23 also has both adaptive and maladaptive roles in mineral abnormalities, cardiovascular morbidity and renal failure progression in chronic kidney disease (CKD). There is an unmet need to develop compounds to mimic and/or inhibit FGF23 functions. FGF23 antagonists would be novel treatment of diseases caused by FGF23 excess, including treatment of hypophosphatemic disorders and prevention of the untoward effects of FGF23 in CKD;conversely, FGF23 agonists could be used to treat hyperphosphatemic disorders and conditions of excess 1,25(OH)2D production. Since there are no known compounds that modulate FGF23 activation of the FGF receptor/a-Klotho complex, we propose a new interdisciplinary team to develop an in-silico program to identify FGF23 agonists and antagonists founded on structure-based computational drug design. This will be performed using leadership- class supercomputers to combine ensemble-based dynamic simulation methods with high-throughput docking. The calculations will make use of an initial "conformational expansion" step to identify targetable conformations of the protein which are then individually targeted by high-throughput supercomputer-based docking calculations. This analysis will generate a prioritized list of potential chemical "hits" that are candidate molecules that directly bind to FGF23 and modify the binding to FGFR/a-Klotho. We will subsequently experimentally screen the computationally-prioritized candidate compounds for FGF receptor/a-Klotho activation or inhibition in a cell-based functional assay and in vivo models. The impact of this interdisciplinary collaboration will be to translate the knowledge of the FGF23 bone-kidney endocrine network to clinical therapies by developing compounds that modulate FGF23 interaction with its receptor complex.
In this application we are employing the power of the supercomputing capacity at Oak Ridge National Laboratory and a new interdisciplinary collaboration between computational scientists at UT/ORNL and biologists and physician-scientists at UTHSC to identify compounds that modulate FGF23 interactions with a-Klotho, the co-factor required for FGF23 activation of FGF receptors. A comprehensive knowledge of targetable conformations of the protein will identify candidate molecules that bind to a-Klotho which will be tested in cell-based assays for their ability to activate or inhibit FGFR/ a-Klotho signaling. These small molecules will be useful tools to manipulate FGF23 signaling and serve as an initial step toward developing pharmaceutical agonists or antagonists modulate the function of the FGF23 endocrine network regulating phosphate and vitamin D metabolism.
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