High Throughput Screening and Molecular Modeling

高通量筛选和分子建模

• 批准号: 7882872
• 负责人: Wayne Guida
• 金额: $ 24.65万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7882872
• 关键词: Biochemical; Bioinformatics; Biological; Biological Assay; Biological Factors; Chemicals; Communication; Data; Data Analyses; Databases; Docking; Future; Goals; Guanine Nucleotide Exchange Factors; Health Services Research; Lead; Maintenance; Malignant Neoplasms; Molecular Models; Molecular Target; Property; Research Personnel; Rho-associated kinase; Screening procedure; Silicon Dioxide; Structure; Surface; Testing; Therapeutic; Work; X-Ray Crystallography; combinatorial; cost effective; database structure; design; drug candidate; high throughput screening; inhibitor/antagonist; molecular modeling; novel; programs; protein geranylgeranyltransferase; rho; small molecule libraries; three dimensional structure; virtual; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Factors; Chemicals; Communication; Data; Data Analyses; Databases; Docking; Future; Goals; Guanine Nucleotide Exchange Factors; Health Services Research; Lead; Maintenance; Malignant Neoplasms; Molecular Models; Molecular Target; Property; Research Personnel; Rho-associated kinase; Screening procedure; Silicon Dioxide; Structure; Surface; Testing; Therapeutic; Work; X-Ray Crystallography; combinatorial; cost effective; database structure; design; drug candidate; high throughput screening; inhibitor/antagonist; molecular modeling; novel; programs; protein geranylgeranyltransferase; rho; small molecule libraries; three dimensional structure; virtual

The primary purpose of the Core B facility is to provide researchers of the NCDDG with rapid and cost effective high throughput screening, molecular modeling, and as a future direction, X-ray crystallography of their targets with the ultimate goal of identifying "hits' for further chemical lead optimization and biological characterization. The Core B facility comprises two functional units: Experimental HTS and Virtual HTS & Molecular Modeling. The two units work closely together to provide complementary approaches toward screening molecular targets. The specific functions of Core B include: (1) Experimental HTS: To design, develop and employ biochemical assays formatted for HTS. To screen the combinatorial chemical libraries prepared by program 1 as well as publicly available chemical libraries, such as NCI Diversity and Natural Product Sets, in order to identify compounds capable of inhibiting the catalytic activities of geranylgeranyltransferase I (GGTase I), Rho guanine nucleotide exchange factors (RhoGEFs) and Rho kinase (ROCK). (2) Virtual HTS: To computationally dock libraries of small molecules from compound databases (>700,000 3D structures) onto defined surfaces of existing crystal structures in order to identify compounds that modulate the catalytic activities of GGTase I and RhoGEFs. (3) Molecular Modeling: The best scoring compounds from virtual screening and, in particular the experimentally confirmed "hits" from virtual screening, as well as those from experimental HTS will be subjected to additional molecular modeling studies. (4) In Silica Prediction of ADME Properties: The QikProp program (Schrodinger, L.L.C.) will be employed to predict ADME properties of "hits" and to optimize ADME properties of potential drug candidates. Data analysis and management: To facilitate communication among programs 1, 2 and 3 and Core A and B, we have set up a centralized database for all related scientific data. The maintenance of the infra-structure of the database is supported by the Moffitt Bioinformatics Services and Research IT (BRIT). Core B will be responsible for the management of the content. The database will allow users a) to register and track all compounds from synthesis/acquiring, shipment to testing; b) to search and review chemical and biological data from Programs 1,2, 3 and Core B.

核心B设施的主要目的是为NCDDG的研究人员提供快速且具有成本效益的高度 吞吐量筛选，分子建模和作为未来方向，其目标的X射线晶体学与 确定“命中”以进一步化学铅优化和生物学表征的最终目标。核心B 设施包括两个功能单元：实验性HTS和虚拟HTS和分子建模。两个单元 紧密合作以提供筛查分子靶标的互补方法。特定功能 核心B包括： （1）实验HTS：设计，开发和采用针对HTS格式的生化测定。要筛选 由程序1编写的组合化学库以及公开可用的化学库， 例如NCI多样性和天然产品集，以识别能够抑制该化合物 黄烷基凝血酶转移酶I（GGTase I），Rho鸟嘌呤核苷酸交换因子的催化活性 （Rhogefs）和Rho激酶（岩石）。 （2）虚拟HTS：到化合物数据库的小分子的计算码头库（> 700,000 3D结构）在现有晶体结构的定义表面上 调节GGTase I和Rhogefs的催化活性。 （3）分子建模：虚拟筛选的最佳评分化合物，尤其是实验 虚拟筛查中确认的“命中”以及实验HTS的“命中”将受到额外的影响 分子建模研究。 （4）在二氧化硅预测中：将采用Qikprop计划（Schrodinger，L.L.C。）来预测 “命中”的ADME性质并优化了潜在药物的ADME特性。 数据分析和管理：为了促进程序1、2和3和核心A和B之间的沟通，我们已经设置 为所有相关科学数据提供集中式数据库。数据库基础结构的维护是 得到莫菲特生物信息学服务和研究（英国）的支持。核心将负责 内容管理。该数据库将允许用户a）注册并跟踪 合成/获取，运输进行测试； b）搜索和审查计划中的化学和生物学数据1,2， 3和核心B。