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The question has been asked how many ligands per WU group. Currently, the answer is less than one, in other words, it takes about three or four work groups to complete a full docking run for one ligand. This docking strategy and parameters was initially chosen to provide a robust method for obtaining accurate predictions of ligand protein orientations. However, as the results and timings from the grid-based docking runs were examined, we have realized that we need to speed up this docking phase of the project in order to reach our goal of finishing the project within a year. Thus, we are adjusting our docking parameters and our database size to speed up the docking runs without sacrificing docking accuracy.

We have selected (and are deploying) a new set of docking parameters that give us good docking predictions for the majority of our tested compounds. These new parameters speed up the docking runs by a few orders of magnitude, but the trade-off is less accurate fits for highly flexible ligands. Ligands that are not highly flexible are still docked accurately with the new parameter set (as judged by test set evaluations to cocrystal strucrtures). Fortunately, the vast majority of lead-like and drug-like molecules are not highly flexible. Thus, we have filtered the ZINC database to remove highly flexible molecules and retain only drug-like and lead-like compounds. This reduces our database to about 3 million compounds, still a sizable number of compounds to examine. With the improved docking parameters and database, each new work group will now contain approximately 10-30 ligands. We expect to screen 3,000,000 ligands against a single protein target every two weeks.

We apologize for the delay in answering this question. We wanted to wait until we could give you a more definitive answer on the changes that we would be making. Thank you again for helping our project.

In response to another question: We avoided using the ZINC fragment library because our synthetic capabilities are limited. Thus, we would have had large delays before testing the computer predictions and identifying drug leads. Instead, we have concentrated on screening compounds that we can obtain quickly, thus speeding up the testing phase of this project.

-Watowich

Thank you for the very detailed response! 3,000,000 ligands per protein every two weeks - wow!!