High Throughput Screening and Molecular Modeling

核心B设施的主要目的是为NCDDG的研究人员提供快速和成本效益高的 吞吐量筛选，分子模拟，并作为未来的方向，他们的目标的X射线结晶学 最终目标是为进一步的化学铅优化和生物学特性确定“HITS”。核心B 该设备包括两个功能单元：实验高温超导和虚拟高温超导与分子建模。这两个单位 密切合作，为筛选分子靶标提供补充方法。具体功能 核心B的价值包括： (1)实验HTS：设计、开发和使用适用于HTS的生化分析方法。要筛选出 由程序1准备的组合化学库以及公开可用的化学库， 例如NCI多样性和自然产物集，以便识别能够抑制 香叶基香叶基转移酶I、Rho鸟嘌呤核苷酸交换因子的催化活性 (RhoGEF)和Rho Kinase(ROCK)。 (2)虚拟HTS：通过计算对接化合物数据库中的小分子文库(&gt；700,000 3D结构)到现有晶体结构的限定表面上，以便识别 调节GGTase I和RhoGEF的催化活性。 (3)分子建模：来自虚拟筛选的最佳评分化合物，特别是实验结果 来自虚拟筛选的确认“命中”，以及来自实验性HTS的命中，将受到额外的 分子建模研究。 (4)在硅胶中预测ADME性质：QIKPROP程序(薛定谔，L.L.C.)将被用来预测 ADME的“HITS”属性和优化潜在候选药物的ADME属性。 数据分析和管理：为了方便程序1、2和3与核心A和B之间的通信，我们设置了 为所有相关的科学数据建立一个集中的数据库。数据库基础设施的维护是 由莫菲特生物信息学服务和研究IT(BRIT)支持。核心B将负责 对内容的管理。该数据库将允许用户a)注册和跟踪来自 合成/获取，运输到测试；b)搜索和审查来自程序1，2， 3和核心B。

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.