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.
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