Research9(1) - Published on Web Structure-Based Design of Selective Agonists for a Rickets-Associated Mutant of the Vitamin D Receptor Steve L

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Structure-Based Design of Selective Agonists for a Rickets-Associated Mutant of the Vitamin D Receptor Steve L. Swann, ² Joel Bergh, Mary C. Farach-Carson, Cory A. Ocasio, ² and John T. Koh* Contribution from the Department of Chemistry and Biochemistry, and the Department of Biological Sciences, Uni V ersity of Delaware, Newark, Delaware 19716 Received May 8, 2002 Abstract: The nuclear and steroid hormone receptors function as ligand-dependent transcriptional regulators of diverse sets of genes associated with development and homeostasis. Mutations to the vitamin D receptor (VDR), a member of the nuclear and steroid hormone receptor family, have been linked to human vitamin D-resistant rickets (hVDRR) and result in high serum 1,25(OH) 2 D 3 concentrations and severe bone underdevelopment. Several hVDRR-associated mutants have been localized to the ligand binding domain of VDR and cause a reduction in or loss of ligand binding and ligand-dependent transactivation function. The missense mutation Arg274 f Leu causes a > 1000-fold reduction in 1,25(OH) 2 D 3 responsiveness and is, therefore, no longer regulated by physiological concentrations of the hormone. In this study, computer- aided molecular design was used to generate a focused library of nonsteroidal analogues of the VDR agonist LG190155 that were uniquely designed to complement the Arg274 f Leu associated with hVDRR. Half of the designed analogues exhibit substantial activity in the hVDRR-associated mutant, whereas none of the structurally similar control compounds exhibited significant activity. The seven most active designed analogues were more than 16 to 526 times more potent than 1,25(OH) 2 D 3 in the mutant receptor (EC 50 ) 3.3 - 121 nM). Significantly, the analogues are selective for the nuclear VDR and did not stimulate cellular calcium influx, which is associated with activation of the membrane-associated vitamin D receptor. The availability of high-resolution protein structures provide us with the unique opportunity to examine the effects of mutations associated with genetic disease at the molecular level. In some rare instances, compounds have been discovered that are able to complement or “rescue” function to genetically impaired proteins. 1 - 3 Genetic diseases associated with mutations to the nuclear and steroid hormone receptors provide many prototypical examples of mutations that reside adjacent to small molecule binding sites that may be amenable to pharmacological rescue with appropriate hormone analogues. Clearly, not all mutations associated with such diseases can be complemented by small molecules. However, the subset of mutations that directly effect hormone recognition present a unique challenge to chemists to develop compounds that may ultimately provide a novel approach for the development of new treatments for genetic disease. The superfamily of nuclear/steroid hormone receptors (NHRs)
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This note was uploaded on 12/04/2011 for the course CHEM 590A taught by Professor Staff during the Summer '10 term at University of Illinois, Urbana Champaign.

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Research9(1) - Published on Web Structure-Based Design of Selective Agonists for a Rickets-Associated Mutant of the Vitamin D Receptor Steve L

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