Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor

项目摘要/摘要 固有无序蛋白质(IDPs)，其缺乏固定的三维结构 生理条件占人类蛋白质组的40%左右，在各种生物中起着至关重要的作用。 生物途径和生物分子组合，并与大量的人类 疾病。随着国内流离失所者填充快速相互转换结构的动态构象集成在 解决方案，不能用单一的主导构象来表示，甚至不能用少量的 大量填充的构象，它们不是传统结构药物的合适靶点 设计方法。如果有可能用小分子药物靶向国内流离失所者，那么可药物的蛋白质组 将大幅扩展，治疗干预目前可能变得可用 无法治愈的疾病 PI的实验室利用集成的计算和实验研究策略来结合 基于核磁共振光谱实验测量的最新全原子分子模拟 和其他生物物理实验，以获得原子描述的动态结合机制的 并利用来自这些绑定机制的见解来预测和合理设计新的绑定 互动。本提案侧重于应用这种计算和实验相结合的方法。 阐明以此为靶点的小分子候选药物的结合机制 雄激素受体的无序结构域，并已进入抗去势前列腺的临床试验 癌症(CRPC)。这些约束机制将被用来通知合理设计更有力和 选择性雄激素受体抑制剂和更有效的CRPC疗法 。本提案描述了一种 在分子研究的分子结合机制之间建立联系的非凡机会 模拟和核磁共振，在细胞分析中观察到的生物学活性，以及来自人类的临床结果 CRPC药物试验。 这项提议将启动一项可持续的长期研究努力，将计算和 研究IDPs在多种细胞和药物中动态相互作用的实验方法 上下文。这项研究工作将刺激强大的平台的发展，以集成计算 和实验方法，这些方法将极大地增加服从结构和 机械特性和药物靶向，将为治疗提供新的途径 对与国内流离失所者异常生物相互作用有关的疾病的干预，例如由 生物分子缩合物的形成和蛋白质的错误折叠。

Project Summary /Abstract Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under physiological conditions, represent ~40% of the human proteome, have crucial functional roles in a variety of biological pathways and biomolecular assemblies and are implicated in a large number of human diseases. As IDPs populate a dynamic conformational ensemble of rapidly interconverting structures in solution, and cannot be represented by a single dominant conformation, or even a small number of substantially populated conformations, they are not suitable targets for conventional structure-based drug design methods. If it becomes possible to target IDPs with small molecule drugs, the druggable proteome will be dramatically expanded and therapeutic interventions may become accessible for currently untreatable diseases The PI’s laboratory utilizes an integrated computational and experimental research strategy to combine state-of-the-art all-atom molecular simulations with experimental measurements from NMR spectroscopy and other biophysical experiments to obtain atomistic descriptions of the dynamic binding mechanisms of IDPs and uses insights form these binding mechanisms to predict and rationally design novel binding interactions. This proposal focuses on applying this integrated computational and experimental approach to elucidate the binding mechanisms of small molecule drug candidates that target that intrinsically disordered domain of the androgen receptor and have entered clinical trials for castration resistant prostate cancer (CRPC). These binding mechanisms will be used to inform the rational design more potent and selective androgen receptor inhibitors and more effective CRPC therapeutics . This proposal describes a remarkable opportunity to draw connections between molecular binding mechanisms studied by molecular simulations and NMR, biological activity observed in cellular assays, and clinical results from human CRPC drug trials. This proposal will initiate a sustainable long-term research effort to combine computational and experimental methods to study the dynamic interactions of IDPs in a variety of cellular and pharmaceutical contexts. This research effort will stimulate the development of robust platforms to integrate computational and experimental methods that will dramatically increase the number of proteins amenable to structural and mechanistic characterization and pharmaceutical targeting and will provide new avenues to therapeutic interventions in diseases associated with aberrant biological interactions of IDPs such as those mediated by biomolecular condensate formation and protein misfolding.