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1alpha,25-dihydroxyvitamin D3 Agonist and Histone Deacetylase Inhibitor Bifunctional Ligand Discovery Virtual Docking, Synthesis, Fluorescence Polarization-Based Screening, and Molecular Dynamics Simulations .

机译：1alpha，25-dihydroxyvitamin D3激动剂和组蛋白脱乙酰基酶抑制剂双功能配体的发现虚拟对接，合成，基于荧光偏振的筛选和分子动力学模拟。

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The vitamin D receptor (VDR) and histone deacetylases (HDACs) are important chemotherapeutic targets. 1,25-dihydroxyvitamin D3 (calcitriol, or 1,25D) is the natural ligand of the VDR, stimulates immune responses, and inhibits cellular proliferation in a number of cancer cell lines. Small molecule HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA, Zolinza; Merck), block angiogenesis and promote cell apoptosis and differentiation and are being investigated as clinical treatments for a wide range of cancers. This thesis describes work on three projects focusing on the VDR and HDAC. In the first project, a hybrid molecule incorporating deacetylase activity into the structure of a 1,25D aromatic analog was identified in a virtual screen using FITTED, a docking program, synthesized, and tested. Surprisingly, it was found to be inactive as an agonist of the VDR. An in silico retrospective analysis of the novel hybrid compound and other non-steroidal VDR ligands revealed several general structural requirements for VDR activity. In a second project, computational modeling techniques including molecular dynamics simulations were employed to understand the differences between two ortho-aminoanilide hybrid compounds, which led one to act as a VDR agonist while the other acted as a VDR antagonist. Finally, as the mechanisms of anticancer activity of HDAC inhibitors are not well understood and current assays for HDAC inhibitors are cumbersome and not generally applicable to all HDAC isoforms, a fluorescence polarization assay for high-throughput screening of HDAC competitive inhibitors was developed. HDAC ligands combining the structures of SAHA and fluorescein were synthesized and determined to be well-suited as a fluorescence polarization assay probe.

机译：维生素D受体（VDR）和组蛋白脱乙酰基酶（HDAC）是重要的化疗靶标。 1,25-二羟基维生素D3（骨化三醇或1,25D）是VDR的天然配体，可刺激免疫反应并抑制许多癌细胞系中的细胞增殖。小分子HDAC抑制剂，例如亚磺酰苯胺异羟肟酸（SAHA，Zolinza; Merck），可阻断血管生成并促进细胞凋亡和分化，目前正在研究其作为多种癌症的临床治疗方法。本文介绍了针对VDR和HDAC的三个项目的工作。在第一个项目中，使用FITTED（对接程序）在虚拟屏幕中识别了将脱乙酰基酶活性掺入1,25D芳香族类似物结构中的杂合分子，进行了合成和测试。令人惊讶地，发现它作为VDR的激动剂是无效的。对该新型杂化化合物和其他非甾体VDR配体的计算机追溯分析显示了VDR活性的一些一般结构要求。在第二个项目中，采用包括分子动力学模拟在内的计算建模技术来了解两种邻氨基苯甲酰胺杂化化合物之间的差异，这导致一种化合物充当VDR激动剂，而另一种充当VDR拮抗剂。最后，由于对HDAC抑制剂的抗癌活性机理尚不十分了解，并且当前的HDAC抑制剂测定方法繁琐且不适用于所有HDAC同工型，因此开发了用于高通量筛选HDAC竞争性抑制剂的荧光偏振测定法。合成了结合SAHA和荧光素结构的HDAC配体，并确定其非常适合用作荧光偏振测定探针。

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作者
Burger, Melanie C.;
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McGill University (Canada).;

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授予单位 McGill University (Canada).;
学科 Chemistry Organic.
学位 M.Sc.
年度 2011
页码 119 p.
总页数 119
原文格式 PDF
正文语种 eng
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1alpha,25-dihydroxyvitamin D3 Agonist and Histone Deacetylase Inhibitor Bifunctional Ligand Discovery Virtual Docking, Synthesis, Fluorescence Polarization-Based Screening, and Molecular Dynamics Simulations .

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