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Dynamic, Structure Driven Fragment Based Design of Selective Androgen Modulators

基于动态结构驱动片段的选择性雄激素调制器设计

基本信息

批准号：
7394311
负责人：
ARNOLD T HAGLER
金额：
$ 28.45万
依托单位：
SHIFA BIOMEDICAL CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-18 至 2010-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7394311
关键词：
AIPC Abbreviations Accounting Active Sites Address Adverse effects Affect Affinity Agonist Algorithms Allosteric Site Androgen Antagonists Androgen Receptor Androgens Antineoplastic Agents Binding Binding Sites Biological Assay Breast Cancer Etiology Cell Proliferation Cell Survival Cells Cessation of life Characteristics Charge Class Clinical Combined Modality Therapy Complex Computer Simulation Disease Disruption Docking Drug Delivery Systems End Point Enzymes Fingerprint Gene Expression Generations Genes Genetic Transcription Goals Growth Hand Helix (Snails)Hormones Institution Interferon Gamma Receptor Beta Chain Lead Ligand Binding Domain Ligands Link Malignant neoplasm of prostate Marketing Methods Mission Molecular Profiling Muscle Muscle Weakness Nuclear Receptors Nucleic Acids Osteoporosis PC3 cell line Peptides Pharmaceutical Preparations Physiological Plant Roots Play Principal Component Analysis Property Prostate Proteins Quantum Mechanics Refractory Resistance Roentgen Rays Role Score Screening procedure Site Staging Stanolone Structure Testing Testosterone Therapeutic Thinking Time Training Work X-Ray Crystallography analog androgen independent prostate cancer base bone cancer cell design desire drug discovery ear helix functional group men molecular dynamics nanometer novel outcome forecast receptor response selective androgen receptor modulator simulation

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, which overcome the ability of all prostate cancers to evolve resistance to current antiandrogen drugs. These changes lead to a poor prognosis and represent a major clinical challenge to the successful treatment of advanced prostate cancer. Prostate cancer (PC) requires the androgen receptor (AR) for growth and proliferation. We will target this receptor as do current marketed antiandrogen drugs. Current drugs all bind to the hormone-binding site (HBS) of AR where they alter the dynamics and structure of the receptor, resulting in an inability of necessary coactivators to bind to the coactivator-binding site (AF-2). A third site has recently been identified -- the BF-3 site -- which, analogous to the hormone site, allosterically affects coactivator binding at the AF-2 site. (The latter allosterically enhances coactivator binding, while ligands at the BF-3 appear to be a negative control). We will exploit this unusual multiplicity of sites in a single drug target to carry out a fragment-based, multi-site, drug discovery strategy that leverages the experimental and theoretical efforts and provides new mechanistic approaches to overcoming advanced PC. To this end we will integrate in silico induced-fit docking with cell based transcription and proliferation assays, X-ray crystallography, and molecular dynamics (MD) simulations to find confirmed hits (X-ray and assays) and determine both structural and dynamic design criteria for lead optimization of compounds at these sites. Project Narrative: The long term goal of this work is to develop novel drugs, targeted to the treatment of advanced prostate cancer, that overcome the ability of prostate cancers to evolve resistance to current drugs within a few years of treatment. Because, there are currently no drugs effective against this advanced form of the disease, prostate cancer is the second leading cause of cancer deaths in men.

描述（由申请人提供）：这项工作的长期目标是开发新的药物，针对晚期前列腺癌的治疗，克服所有前列腺癌对当前抗雄激素药物产生耐药性的能力。这些变化导致预后不良，是成功治疗晚期前列腺癌的主要临床挑战。前列腺癌（PC）的生长和增殖需要雄激素受体（AR）。我们将像目前上市的抗雄激素药物一样靶向这种受体。目前的药物都与AR的激素结合位点（HBS）结合，在那里它们改变受体的动力学和结构，导致必要的辅激活剂无法与辅激活剂结合位点（AF-2）结合。最近发现了第三个位点——BF-3位点，它与激素位点类似，以变构的方式影响AF-2位点的共激活物结合。（后者变构增强了辅激活剂的结合，而BF-3的配体似乎是一个负对照）。我们将利用单个药物靶标中这种不寻常的位点多样性来开展基于片段的多位点药物发现策略，利用实验和理论的努力，并提供新的机制方法来克服先进的PC。为此，我们将结合基于细胞的转录和增殖试验、x射线晶体学和分子动力学（MD）模拟，进行硅诱导匹配对接，以找到确认的命中点（x射线和试验），并确定这些位点上先导化合物优化的结构和动态设计标准。