Multi-scale Simulations of Bronic Acids in Prteasome Inhibition and Saccharide

布朗酸在蛋白酶体抑制和糖中的多尺度模拟

• 批准号: 8811251
• 负责人: Joseph Dennis Larkin
• 金额: $ 24.9万
• 依托单位: ECKERD COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811251
• 关键词: Acids; Active Sites; Adverse reactions; Advisory Committees; Affinity; Aftercare; Algorithms; Aluminum; Antioxidants; Area; Ascorbic Acid; Attention; Award; Binding; Binding Sites; Biological; Biological Models; Biology; Boron; Boronic Acids; Bortezomib; Cataloging; Catalogs; Chemical Agents; Chemical Structure; Chemicals; Chemistry; Complex; Computational Biology; Computer Simulation; Computer software; Cytochrome P450; Detection; Development; Discipline; Disease; Doctor of Philosophy; Education; Educational workshop; Ensure; FDA approved; Fluorescence; Fructose; Future; Galactose; Glucose; Glutathione; Glutathione Reductase; Glutathionylspermidine synthase; Glycoproteins; Goals; Grant; Industry; K-Series Research Career Programs; Laboratories; Length; Liver Microsomes; Malignant Neoplasms; Mechanics; Medical; Mentors; Metabolism; Methodology; Methods; Modeling; Molecular; Molecular Structure; Nitrogen; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Property; Proteasome Inhibition; Proteasome Inhibitor; Proteins; Reaction; Reactive Oxygen Species; Recommendation; Relative (related person); Reporter; Research; Research Training; Resistance; Role; Route; Schools; Science; Silicon; Specificity; Spermidine Synthase; Sucrose; System; Techniques; Testing; Thermodynamics; Threonine; Tiron; Training; Training and Education; United States National Institutes of Health; Universities; Water; Work; Writing; base; cancer therapy; chemical property; chemical reaction; chemotherapy; computational chemistry; computer program; covalent bond; design; diabetic; experience; field study; flexibility; fluorophore; functional group; glucose monitor; glucose receptor; insight; macromolecule; mathematical model; meetings; monitoring device; multi-scale modeling; multicatalytic endopeptidase complex; novel; post-doctoral training; prevent; professor; programs; quantum; receptor; repository; research study; restraint; sensor; simulation; sugar; tool

The candidate earned a Ph.D. in chemistry from the University of Georgia working under the direction of Henry F. Schaefer, Graham-Perdue Professor of Chemistry. Research performed during graduate school focused on the application of quantum mechanical (QM) methods to determine thermodynamic, spectroscopic, and structural properties of silicon and aluminum complexes. This graduate work led to the identification of highly accurate methods for use in specific molecular systems and has continued through post-doctoral training. The candidate's post-doctoral work has further extended his expertise in QM computations to boron containing molecules that rely on specific approaches due to their unique chemistry. The proposed computations will build on the candidate's background in QM methodology and provide new experience in methods to study larger macromolecules. The Research Plan will investigate the chemistry governing boronic acid (BA) based proteasome inhibition and saccharide sensing. Boronic acids have emerged as important chemical structures for use in a number of potential medical and biological applications. Chemical interactions related to these fields will be studied with the following: Mixed Quantum Mechanical/Molecular Mechanical (QM/MM) methods and mathematical modeling of reaction pathways accessed via the new Multi-Scale interface implemented in the CHARMM software suite of programs. These methods represent a new field of study for the candidate and will broaden his expertise significantly. Specifically, these computations will investigate BA based inhibition of proteasomes. Despite their promise in the treatment of a myriad of cancers, this inhibitory effect is not fully understood. Furthermore, there is an increase in chemoresistance of the only FDA approved proteasome inhibitor, Bortezoniib (a dipeptidyl-boronic acid). Determining the cause of this increased resistance and the chemical interactions of BAs in the binding pocket will provide valuable insight for future proteasome inhibitors. Three possible reasons for this resistance will be explored. These include: (1) understanding the chemical reactions for the metabolism of bortezomib, (2) adverse reactions through conjugation therapy from supplements that oxidize bortezomib, and (3) the potential inhibition of glutathionyl spermidine synthase that may potentially cause an increase in glutathione, a known target of resistance suppressing conjugates. Boronic acids have also been shown to be excellent synthetic fluorescent markers for saccharides. This proposal also plans to use QM/MM methods to understand the chemical interactions of boronic acid-sugar complexes in an attempt to develop saccharide specific sensors in a modular fashion. Results will be used to design synthetic receptors for the identification of sugar units in glycans that are representative of disease states. The Career Development Award will aid the candidate in mastering the necessary tools for these studies through continued training in the Laboratory of Computational Biology within the NlH/NHLBl. Previous postdoctoral research focused on highly accurate computation of chemical properties of smaller boronic acid model systems using QM only approaches. This award will facilitate a transition into multiple length scale (Multi- Scale) QM/MM modeling using reaction pathway techniques not currently in the candidate's repertoire. Multi- Scale simulations represent a highly significant, new area of study that bridge many computational disciplines. This award will help to establish the candidate as a leader in this new field. Additional practical experience will include the ability to modify, through computer programming, the complex computer program CHARMM. In addition to being a comprehensive biological modeling platform, CHARMM also serves as a repository for the newest algorithms in the field of computational biology and chemistry. The candidate will gain valuable experience by refining and advancing reaction path methodology during the award period. In addition to research training, further education during the award period will consist of attending grant-writing workshops and biology focused classes offered through the Office of Intramural Training and Education (OITE) at the NIH. The candidates Advisory Committee will meet annually to discuss progress and to ensure that the proposed goals are met, making recommendations where needed. Weekly meetings with the candidate's mentor will also be invaluable. This support will keep the candidate on track to successfully transition to an independent research position.

该候选人获得了博士学位。乔治亚大学化学博士，在 Henry 的指导下工作 F. Schaefer，Graham-Perdue 化学教授。研究生期间进行的研究重点是 应用量子力学 (QM) 方法来确定热力学、光谱和 硅和铝配合物的结构特性。这项研究生工作导致了高度的鉴定 在特定分子系统中使用的准确方法，并通过博士后培训继续进行。这 候选人的博士后工作进一步将他在 QM 计算方面的专业知识扩展到含硼 由于其独特的化学性质，依赖于特定方法的分子。 拟议的计算将建立在候选人的质量管理方法背景之上，并提供新的 研究较大大分子的方法的经验。该研究计划将调查化学 控制基于硼酸（BA）的蛋白酶体抑制和糖传感。硼酸具有 已成为重要的化学结构，可用于许多潜在的医学和生物应用。 与这些领域相关的化学相互作用将通过以下内容进行研究：混合量子 机械/分子力学 (QM/MM) 方法和反应途径的数学建模 通过 CHARMM 软件程序套件中实现的新多尺度接口进行访问。这些 方法代表了候选人的一个新的研究领域，并将显着拓宽他的专业知识。 具体来说，这些计算将研究基于 BA 的蛋白酶体抑制。尽管他们承诺 在多种癌症的治疗中，这种抑制作用尚不完全清楚。此外，还有一个 增加 FDA 唯一批准的蛋白酶体抑制剂 Bortezoniib（一种二肽基硼酸）的化疗耐药性 酸）。确定这种耐药性增加的原因以及结合中 BA 的化学相互作用 pocket 将为未来的蛋白酶体抑制剂提供有价值的见解。这种阻力的三个可能原因 将被探索。其中包括：(1) 了解硼替佐米代谢的化学反应，(2) 通过氧化硼替佐米补充剂的结合疗法产生的不良反应，以及（3）潜在的 抑制谷胱甘肽亚精胺合酶，可能会导致谷胱甘肽增加，谷胱甘肽是一种已知的 抗性抑制缀合物的靶标。 硼酸也被证明是优秀的糖类合成荧光标记物。这 该提案还计划使用 QM/MM 方法来了解硼酸-糖的化学相互作用 复合物试图以模块化方式开发糖类特异性传感器。结果将用于 设计合成受体来识别代表疾病的聚糖中的糖单元 州。 职业发展奖将帮助候选人掌握这些研究所需的工具 通过在 NlH/NHLBl 计算生物学实验室的继续培训。以前的博士后 研究重点是较小硼酸模型化学性质的高精度计算 仅使用 QM 方法的系统。该奖项将促进向多长度尺度（多尺度）的过渡 规模）使用反应途径技术进行 QM/MM 建模，目前该技术尚未包含在候选人的技能范围内。多- 尺度模拟代表了一个非常重要的新研究领域，它连接了许多计算学科。 该奖项将有助于使候选人成为这个新领域的领导者。额外的实践经验将 包括通过计算机编程修改复杂计算机程序 CHARMM 的能力。在 除了作为一个全面的生物建模平台之外，CHARMM 还可以作为 计算生物学和化学领域的最新算法。候选人将获得宝贵的 获奖期间通过完善和推进反应路径方法学获得的经验。 除了研究培训外，奖励期间的继续教育将包括参加资助写作 通过校内培训和教育办公室 (OITE) 提供的讲习班和生物学重点课程 在美国国立卫生研究院。候选人咨询委员会将每年举行一次会议，讨论进展情况并确保 实现提出的目标，并在需要时提出建议。每周与候选人的会议 导师也将是无价的。这种支持将使候选人能够成功过渡到 独立研究职位。