High Throughput Screening & Molecular Modeling

高通量筛选

• 批准号: 7214571
• 负责人: Wayne Guida
• 金额: $ 18.59万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7214571
• 关键词: Biological; Biological Assay; Biological Factors; Chemicals; Collection; Communication; Core Facility; Data; Data Analyses; Databases; Evaluation; Goals; Housing; Laboratories; Lead; Libraries; MDM2 gene; MDM2 gene; Maintenance; PTPN11 gene; Pharmaceutical Preparations; Process; Property; Purpose; Quantitative Structure-Activity Relationship; Research Personnel; Resources; Roentgen Rays; Score; Screening procedure; Silicon Dioxide; Structure; Testing; Work; base; chymotrypsin; computer program; cost effective; high throughput screening; molecular modeling; multicatalytic endopeptidase complex; small molecule libraries; three-dimensional modeling; virtual

The primary purpose of the Core B facility is to provide researchers of the P01 with rapid and cost effective high throughput screening and molecular modeling 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 biomolecular targets and toward aiding the lead optimization process by serving as a resource for molecular modeling studies. The specific functions of Core B include: 1) Experimental HTS: To screen the chemical libraries prepared by projects 1, 2, 3, 4 and 5 as well as in-house chemical libraries to identify compounds capable of inhibiting SHP2 and chymotrypsin-like proteasome activities as well as Rb/Raf, Bcl-xL/Bax and MDM2/MDMX/p53 associations. Our in-house chemical libraries include the publicly available NCI Diversity, Natural Product, Challenge and Mechanistic Sets as well as a 20,000 diverse chemical compound library we purchased from Chemical Diversity Labs (ChemDiv). The 20,000 compounds were selected from ChemDiv's ~600,000 compound collection, which consists of ChemDiv's internal synthesis efforts as well as procurement from laboratories around the world , to represent maximal chemical and structural diversity. Experimental assays will also be preformed for the evaluation of ADME properties. 2) Virtual HTS: To search compound databases (-650,000 3D models) based on the X-ray or NMR structures of SHP2, MDM2, Bcl-xL and the chymotrypsin-like subunit of the proteasome. 3) Molecular Modeling: The best scoring compounds from virtual screening and, in particular the experimentally confirmed "hits" from virtual screening, will be subjected to additional molecular modeling studies including 3D QSAR analysis to aid the lead optimization process. 4) Prediction of ADME Properties: The QikProp computer program (Schrodinger, L.L.C.) will be employed for the in silica prediction of ADME properties of "hits" and to optimize ADME properties of potential drug candidates. 5) Data analysis and management: To facilitate communication among projects 1, 2, 3, 4 and 5 and Core A, B and C, 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 IT Core Facility. Core B will be responsible for the management of the content of the databases. The database will allow users a) to register and track all compounds prepared by projects 1,2,3,4 and 5 from synthesis/acquiring, shipment to testing; b) to search and review chemical and biological data from projects 1, 2, 3, 4, 5 and Core B and C.

核心B设施的主要目的是为P01的研究人员提供快速和成本效益 其目标的高吞吐量筛选和分子建模，其最终目标是确定“命中” 用于进一步的化学铅优化和生物学特征。核心B设施包括两个 功能单元：实验性HTS和虚拟HTS/分子建模。这两个单元紧密合作 提供互补的方法来筛选生物分子靶标并帮助铅 通过作为分子建模研究的资源来优化过程。核心的特定功能 B包括：1）实验HTS：筛选项目1、2、3、4和5准备的化学库 以及内部化学库，以识别能够抑制SHP2和类似辣椒蛋白的化合物 蛋白酶体活动以及RB/RAF，BCL-XL/BAX和MDM2/MDMX/p53关联。我们的内部 化学库包括公开可用的NCI多样性，天然产品，挑战和机械 我们从化学多样性实验室购买的套件以及20,000种不同的化合物库 （Chemdiv）。从Chemdiv的约600,000种化合物中选择了20,000种化合物，这些化合物是 包括Chemdiv的内部合成工作以及来自世界各地的实验室的采购 代表最大化学和结构多样性。实验测定也将用于 评估ADME属性。 2）虚拟HTS：搜索化合物数据库（-650,000 3D型号） 基于SHP2，MDM2，BCL-XL的X射线或NMR结构，以及类似胰凝乳蛋白酶的亚基 蛋白酶体。 3）分子建模：虚拟筛选，尤其是从 实验确认的虚拟筛选“命中”将进行其他分子建模 研究包括3D QSAR分析，以帮助铅优化过程。 4）ADME属性的预测： Qikprop计算机程序（Schrodinger，L.L.C。）将用于二氧化硅预测 “命中”的性质并优化潜在药物的ADME特性。 5）数据分析和 管理：为了促进项目1、2、3、4和5和核心A，B和C之间的沟通，我们已经设置了 为所有相关科学数据的集中式数据库，维护的基础结构 数据库由Moffitt IT核心设施支持。核心B将负责管理 数据库的内容。该数据库将允许用户a）注册并跟踪由 从合成/收购，运输到测试的1,2,3,4和5项目； b）搜索和审查化学物质和 项目1、2、3、4、5和核心B和C的生物数据。