A Web-Based Automatic Molecular Docking System

描述(由申请人提供)：尽管众所周知的算法缺陷，分子对接筛选在最近几年已经取得了重要的成功，现在是利用结构来发现配体的最实用的技术。不幸的是，进入壁垒在很大程度上限制了专家及其合作者使用这项技术。对接数据库的获取成本很高，需要相当大的操作，而且软件也很复杂。这降低了这项技术的影响，并限制了它可以应用于的问题的种类。我们建议开发工具和数据库，以BLAST的精神将对接带给广泛的受众，并允许将其应用于新的问题。具体目标是；目标1。建立公共对接服务作为研究工具。1.开发适用于对接的公共数据库：a.一个有500,000种商业上可获得的“类药物”化合物的数据库，b.一个有注释的代谢物数据库。2.开发一个界面，允许非专家对照目标结构筛选这些数据库。3.开发脚本以完全自动化停靠过程。4.开发计算平台，实现分布式计算。目标2.创建基于网络的分析工具，包括得分最高的配体数据库。1.开发自动化、交互式、视觉丰富和直观的工具来分析对接结果：a.结果浏览器，以便于对购买和测试的得分最高的命中进行优先排序；b.到分子图形查看器的链接，以检查对接姿势；c.丰富图，以说明已知配体列表的良好得分程度；d.监视和诊断数千个高通量自动计算所需的对接计算的高级摘要、摘要和统计数据。2.建立1000多个已知和未知功能的蛋白质结合位点的高分对接配体数据库。使此数据库在Web上可用。3.开发基于网络的工具来比较绑定站点对之间得分最高的命中列表。广泛的初步结果表明，这些目标是可行的。

DESCRIPTION (provided by applicant): Notwithstanding well-known algorithmic weaknesses, molecular docking screens have had important successes in recent years, and are now the most practical technique to leverage structure for ligand discovery. Unfortunately, barriers to entry have largely restricted the techniques to experts and their collaborators. Docking databases are expensive to acquire, require considerable manipulation, and the software is byzantine. This has diminished the impact of the technique and limited the sorts of problems to which it can be applied. We propose to develop tools and databases that will bring docking to a broad audience, in the spirit of BLAST, and allow its application to new questions. The specific aims are; Aim 1. To build a public docking service as a research tool. 1. Develop public databases suitable for docking: a. A database of 500,000 commercially available, "drug-like" compounds, b. A database of annotated metabolites. 2. Develop an interface to allow non-experts to screen these databases against target structures. 3. Develop scripts to completely automate the docking procedure. 4. Develop a computational platform to distribute the calculations. Aim 2. To create web-based analysis tools including a database of top scoring ligands. 1. Develop automated, interactive, visually rich and intuitive tools to analyze docking results: a. A results browser to facilitate prioritizing top scoring hits for purchasing and testing, b. Links to molecular graphics viewers to examine docked poses, c. Enrichment plots to illustrate the degree to which lists of known ligands score well, d. High level summaries, digests and statistics of docking calculations required for monitoring and diagnosing thousands of high-throughput automatic calculations. 2. Develop a database of top scoring docked ligands for over 1000 protein binding sites of both known and unknown function. Make this database available on the web. 3. Develop web-based tools to compare top scoring hit lists between pairs of binding sites. Extensive preliminary results suggest that these aims are feasible.