High Throughput Screening & Molecular Modeling

核心B设施的主要目的是为P01的研究人员提供快速和具有成本效益的 其目标的高通量筛选和分子建模，最终目标是鉴定“命中” 用于进一步的化学铅优化和生物表征。核心B设施包括两个 功能单元：实验HTS和虚拟HTS/分子建模。两个单位密切合作 提供筛选生物分子靶点和帮助领导的补充方法 优化过程作为分子建模研究的资源。核心的具体功能 B包括：1）实验HTS：筛选由项目1、2、3、4和5制备的化学文库， 以及内部化学文库，以鉴定能够抑制SHP 2和胰凝乳蛋白酶样蛋白酶的化合物。 蛋白酶体活性以及Rb/Raf、Bcl-xL/Bax和MDM 2/MDMX/p53关联。我们的内部 化学图书馆包括公开的NCI多样性，天然产物，挑战和机制 以及我们从化学多样性实验室购买的20，000种不同的化合物库 （ChemDiv）.这20，000种化合物选自ChemDiv的约600，000种化合物， 包括ChemDiv的内部合成工作以及从世界各地的实验室采购， 来代表最大的化学和结构多样性。还将进行实验分析， ADME属性的评估。2)虚拟HTS：搜索化合物数据库（约650，000个3D模型） 基于SHP 2、MDM 2、Bcl-xL和胰凝乳蛋白酶样亚基的X射线或NMR结构， 蛋白酶体3)分子建模：来自虚拟筛选的最佳得分化合物， 从虚拟筛选中实验确认的“命中”，将进行额外的分子建模 研究包括3D QSAR分析，以帮助电极导线优化过程。4)ADME性质的预测： QikProp计算机程序（Schrodinger，L.L.C.）将用于ADME的二氧化硅预测 因此，本发明的目的在于提供“命中”的ADME性质和优化潜在候选药物的ADME性质。5)数据分析和 管理：为了促进项目1、2、3、4和5以及核心A、B和C之间的沟通，我们制定了 建立一个所有相关科学数据的中央数据库， 数据库由莫菲特IT核心设施提供支持。核心B将负责管理 数据库的内容。该数据库将允许用户a）登记和跟踪所有化合物， 项目1、2、3、4和5从合成/获取、装运到测试; B）搜索和审查化学品， 来自项目1、2、3、4、5和核心B和C的生物学数据。

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.