A Web-Based Automatic Molecular Docking System

描述（由申请人提供）：尽管存在众所周知的算法缺陷，分子对接筛选近年来取得了重要的成功，并且现在是利用结构发现配体的最实用技术。不幸的是，进入壁垒在很大程度上限制了专家和他们的合作者使用这些技术。对接数据库的成本很高，需要大量的操作，而且软件也很复杂。这削弱了该技术的影响，限制了它可以应用的问题种类。我们建议开发工具和数据库，将对接带给广泛的受众，本着BLAST的精神，并允许其应用于新的问题。具体目标是；目的1。以构建公共对接服务为研究工具。1. 开发适合对接的公共数据库：a.拥有50万个商业上可获得的“类似药物”化合物的数据库；b.带有注释的代谢物数据库。2. 开发一个接口，允许非专家根据目标结构筛选这些数据库。3. 开发脚本，使对接过程完全自动化。4. 开发一个计算平台来分发计算结果。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、直观的对接结果分析工具；a.一个结果浏览器，方便优先考虑购买和测试的得分最高的命中，b.链接到分子图形查看器，以检查对接姿势，c.浓缩图，以说明已知配体列表得分良好的程度，d.监测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。2. 为超过1000个已知和未知功能的蛋白质结合位点建立一个得分最高的对接配体数据库。把这个数据库放到网上。3. 开发基于网络的工具来比较结合位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.