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: 8837057
• 负责人: Joseph Dennis Larkin
• 金额: $ 21.84万
• 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/8837057
• 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.

候选人获得了博士学位。格鲁吉亚大学的化学系， F. Schaefer，Graham-Perdue化学教授。研究生期间进行的研究集中在 量子力学（QM）方法的应用，以确定热力学，光谱， 硅和铝络合物的结构性质。这项研究工作导致了高度的识别 在特定的分子系统中使用精确的方法，并继续通过博士后培训。的 候选人的博士后工作进一步扩展了他在QM计算的专业知识，以含硼 分子由于其独特的化学性质而依赖于特定的方法。 建议的计算将建立在候选人的背景质量管理方法，并提供新的 研究大分子方法的经验。研究计划将研究化学 控制基于硼酸（BA）的蛋白酶体抑制和糖传感。硼酸具有 作为重要的化学结构出现，用于许多潜在的医学和生物学应用。 与这些领域相关的化学相互作用将通过以下方式进行研究： 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界面访问。这些 方法对候选人来说是一个新的研究领域，将大大拓宽他的专业知识。 具体而言，这些计算将研究基于BA的蛋白酶体抑制。尽管他们的承诺， 尽管这种抑制作用被广泛应用于治疗无数癌症，但目前还没有完全了解。此外，还有一个 唯一一种FDA批准的蛋白酶体抑制剂Bortezonib（二肽基硼酸盐）的耐药性增加 酸）。确定这种增加的阻力的原因和结合中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。这些包括：（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治疗产生的不良反应，以及（3）潜在的 谷胱甘肽亚精胺合酶的抑制可能会导致谷胱甘肽的增加，这是一种已知的 抗性抑制缀合物的靶标。 硼酸也已被证明是极好的合成荧光标记物。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，试图以模块化的方式开发糖特异性传感器。结果将用于 设计合成受体，用于识别代表疾病的聚糖中的糖单位 states. 职业发展奖将帮助候选人掌握这些研究的必要工具 通过在NIH/NHLBI内的计算生物学实验室的持续培训。前博士后 研究集中在更小硼酸模型的化学性质的高精度计算上 仅使用QM方法的系统。该奖项将促进过渡到多长度规模（多， 规模）QM/MM建模使用的反应途径技术，目前没有在候选人的剧目。多重 尺度模拟是一个非常重要的新的研究领域，它连接了许多计算学科。 这个奖项将有助于建立候选人作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，CHARMM还作为一个存储库， 计算生物学和化学领域的最新算法。候选人将获得宝贵的 在授予期间，通过完善和推进反应路径方法学，积累了丰富的经验。 除了研究培训外，在获奖期间的进一步教育将包括参加赠款写作 通过校内培训和教育办公室（OITE）提供的研讨会和生物学课程 在国家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 实现拟议目标，并在需要时提出建议。每周与候选人的 导师也将是无价的。这种支持将使候选人顺利过渡到 独立研究立场。