Dynamic, Structure Driven Fragment Based Design of Selective Androgen Modulators

描述（由申请人提供）：这项工作的长期目标是开发靶向治疗晚期前列腺癌的新药，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，并代表了成功治疗晚期前列腺癌的主要临床挑战。前列腺癌（PC）需要雄激素受体（AR）的生长和增殖。我们将像目前市售的抗雄激素药物一样靶向该受体。目前的药物都结合到AR的酶结合位点（HBS），在那里它们改变受体的动力学和结构，导致必需的辅激活剂不能结合到辅激活剂结合位点（AF-2）。第三个网站最近已被确定-BF-3网站-这，类似于激素网站，变构影响辅激活剂结合AF-2网站。(The后者变构地增强共激活因子结合，而BF-3处的配体似乎是阴性对照）。我们将利用这种不寻常的多个位点在一个单一的药物靶点进行片段为基础的，多位点的药物发现策略，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，我们将在计算机上集成诱导适合对接与基于细胞的转录和增殖测定，X射线晶体学和分子动力学（MD）模拟，以找到确认的命中（X射线和测定），并确定在这些网站的化合物的铅优化的结构和动态设计标准。 项目叙述：这项工作的长期目标是开发针对晚期前列腺癌治疗的新药，克服前列腺癌在治疗几年内对当前药物产生耐药性的能力。因为目前还没有有效的药物来治疗这种晚期疾病，前列腺癌是男性癌症死亡的第二大原因。

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.