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

表征去势抵抗性前列腺癌治疗药物与雄激素受体本质上无序的 N 端结构域的结合机制

• 批准号: 10275183
• 负责人: Paul Robustelli
• 金额: $ 34.17万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10275183
• 关键词: Androgen Receptor; Antineoplastic Agents; Binding; Biological; Biophysics; Cellular Assay; Clinical; Clinical Trials; Development; Disease; Drug Design; Drug Targeting; Human; Laboratories; Measurement; Mediating; Methods; Molecular; Molecular Conformation; N-terminal; NMR Spectroscopy; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Proteins; Proteome; Research; Role; Structure; Therapeutic; Therapeutic Intervention; Work; base; castration resistant prostate cancer; design; drug candidate; experimental study; human disease; inhibitor/antagonist; insight; novel; protein misfolding; simulation; small molecule; therapeutic target; three dimensional structure

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.

项目总结/摘要 内含子无序蛋白（IDP），其缺乏固定的三维结构， 生理条件下，代表约40%的人类蛋白质组，在各种各样的功能中发挥着至关重要的作用。 生物途径和生物分子组装，并涉及大量的人类 疾病当IDP在细胞中填充快速相互转换结构的动态构象集合时， 解决方案，不能由一个单一的优势构象，甚至是少量的 由于它们具有基本上密集的构象，因此它们不是常规的基于结构的药物的合适靶点 设计方法如果可以用小分子药物靶向IDP， 将大大扩大，治疗干预可能成为目前 不治之症 PI的实验室利用综合计算和实验研究策略，将联合收割机 最先进的全原子分子模拟与NMR光谱实验测量 和其他生物物理实验，以获得原子的动态结合机制的描述， IDPs和使用这些结合机制的见解来预测和合理设计新的结合 交互.这项建议的重点是应用这种综合计算和实验的方法 为了阐明小分子候选药物的结合机制， 雄激素受体的紊乱结构域，并已进入去势抵抗性前列腺的临床试验 癌症（CRPC）。这些绑定机制将被用来通知理性设计更有效， 选择性雄激素受体抑制剂和更有效的CRPC治疗 .该提案描述了一个 这是一个了不起的机会，可以将分子结合机制与分子生物学研究的分子结合机制联系起来。 模拟和NMR，在细胞测定中观察到的生物活性，以及来自人类的临床结果。 CRPC药物试验。 这项提案将启动一项可持续的长期研究工作，将联合收割机的计算和 实验方法来研究各种细胞和药物中IDP的动态相互作用， contexts.这项研究工作将刺激强大的平台的发展，以整合计算 和实验方法，这将大大增加蛋白质的数量， 机制表征和药物靶向，并将提供新的途径，以治疗 干预与国内流离失所者异常生物相互作用有关的疾病，例如 生物分子冷凝物形成和蛋白质错误折叠。