D-EXP020

=Docking Ugi Products Against Tubulin Using SwissDock=

Researchers
Aurélien Grosdidier (Swiss Institute of Bioinformatics) Vincent Zoete (Swiss Institute of Bioinformatics) Jean-Claude Bradley (Drexel University) Andrew SID Lang (Oral Roberts University)

Objective
To dock CombiUgi library 7 (15.7 Mb, 117450 Ugi products) against tubulin using SwissDock. All of the compounds in this library have starting materials in abundance in the Bradley lab as of 07/22/2009.

Background
SwissDock is a "web service to predict the molecular interactions that may occur between a target protein and a small molecule." The Bradley group investigated using the SwissDock webservice to dock library7 against tubulin, see @D-EXP018 for a similar run using vina. Upon investigation and with communication with the developers, it was found that SwissDock is designed for docking a single (or small group of ligands) against a protein and that it would be difficult to use SwissDock as a webservice to run the entire 117,450 compounds of library7. Discussion then followed about a possible collaboration - using the SwissDock technology and expertise at the Swiss Institute of Bioinformatics to dock library7 against tubulin offline at SIB.

Preliminary Run
The SIB group docked paclitaxel against tubulin, as we did in the first run of D-EXP018, using both the "very fast" and "accurate" parameter sets of SwissDock, including the entire protein in the search space. Native binding modes of paclitaxel were reproduced in both cases (rmsd around 4Å). The input files for the ligand, protein, and the predicted pdb, dock4 and chimera session can be found here:. While performing docking the SIB group noticed that the the first run of D-EXP018 was limited to the binding pocket and that docking this way will force new molecules to be docked in the same pocket which could be different than any experimental binding mode. Also the SIB group found potential issues with the 3D structure of 1JFF, the target we are using. First, it has a resolution of 3.7Å and that a higher resolution (1.5Å - 2Å) would be better to use. Second, that the amino acids next to the paclitaxel were reconstructed around it, thus creating a strong induced fit. This could potentially penalize the docking of other compounds.