D-EXP022

Docking Dibenzalacetone Derivatives Against Tubulin Using PaDEL-ADV

 * Researchers: Andrew SID Lang, Jean-Claude Bradley, Matthew J McBride, and Anthony J Williams**

**Objective**
To dock 325 d ibenzalacetone derivatives (library 12) against tubulin in order to find replacement candidates for taxol (paclitaxel) that are easier (and cheaper) to synthesize from common starting materials found in abundance in the Bradley lab 2012-07-13.

Procedure
We followed the same procedure for docking with PaDEL-ADV as in Docking Run 19 1. We collated the product SMILES into a single file 2. We converted the SMILES to a collection of potential ligands (3D pdb files - correctly protonated) using ChemAxon's molconvert code molconvert -3 pdb:H lib012.smi -m -o lib12ligand.pdb code 3. We performed docking using PaDEL-ADV - virtual screening completed in 4 hrs 39.5 mins (51s/mol)

Results
The for all compounds in the library ranged from -10.3 to -5.8. The top ten candidates being: Note that all these products are predicted to have low aqueous solubility (and predicted logP > 5 - a rule of 5 violation) as compared to the library as a whole, which ranges from -3.22 to -9.22 (our top hit). This low aqueous solubility is a concern as one of the reason why we are trying to find an alternative to taxol is its low aqueous solubility is a problem for delivery.
 * Key || CSID || Product || Aldehyde One || Aldehyde Two || MW || VCClogP || VCClogS || ONSMP010 mpC || Taxol Binding Affinity ||
 * 1 || 28190813 || O=C(\C=C\c2cc3c(c1c2cccc1)cccc3)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc2cc3c(c1c2cccc1)cccc3 || O=Cc2cc3c(c1c2cccc1)cccc3 || 434.17 || 8.09 || -9.22 || 212 || -10.3 ||
 * 7 || NA || O=C(\C=C\c2ccc1c(cccc1)c2)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc2ccc1c(cccc1)c2 || O=Cc2cc3c(c1c2cccc1)cccc3 || 384.15 || 7.32 || -8.87 || 207 || -9.9 ||
 * 29 || NA || O=C(\C=C\c1c2c(ccc1OC)cccc2)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1c2c(ccc1OC)cccc2 || O=Cc2cc3c(c1c2cccc1)cccc3 || 414.16 || 7.14 || -8.82 || 187 || -9.6 ||
 * 37 || NA || O=C(\C=C\c1c2c(c(OC)cc1)ccc(OC)c2)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1c2c(c(OC)cc1)ccc(OC)c2 || O=Cc2cc3c(c1c2cccc1)cccc3 || 444.17 || 7.13 || -8.73 || 172 || -9.6 ||
 * 56 || NA || O=C(\C=C\c1ccc(C)cc1C)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1ccc(C)cc1C || O=Cc2cc3c(c1c2cccc1)cccc3 || 362.17 || 6.73 || -8.57 || 173 || -9.4 ||
 * 79 || NA || O=C(\C=C\c1ccc(C(F)(F)(F))cc1)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1ccc(C(F)(F)(F))cc1 || O=Cc2cc3c(c1c2cccc1)cccc3 || 402.12 || 6.61 || -7.81 || 174 || -9.4 ||
 * 10 || 4523376 || O=C(\C=C\c2ccc1c(cccc1)c2)\C=C\c2ccc1c(cccc1)c2 || O=Cc2ccc1c(cccc1)c2 || O=Cc2ccc1c(cccc1)c2 || 334.14 || 6.34 || -8.12 || 192 || -9.3 ||
 * 92 || NA || O=C(\C=C\c1cc(OC)ccc1)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1cc(OC)ccc1 || O=Cc2cc3c(c1c2cccc1)cccc3 || 364.15 || 6.31 || -8.13 || 175 || -9.3 ||
 * 191 || NA || O=C(\C=C\c1cc(ccc1Cl)[N+]([O-])=O)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1cc(ccc1Cl)[N+]([O-])=O || O=Cc2cc3c(c1c2cccc1)cccc3 || 413.08 || 6.72 || -8.25 || 175 || -9.3 ||
 * 301 || NA || O=C(\C=C\c1ccc2OCOc2c1)\C=C\c2cc3c(c1c2cccc1)cccc3 || O=Cc1ccc2OCOc2c1 || O=Cc2cc3c(c1c2cccc1)cccc3 || 378.13 || 5.9 || -7.8 || 183 || -9.3 ||

The top ligand is shown docked in the image below

Conclusion
Comparing the range of the top 10 ligand affinities for library12 (-9.3 to -10.3) with those of other docking runs: library7 - 117450 Ugi products (-10.9 to -11.4), library8 - 2175 Ugi products with the chiral side chain to paclitaxel (-9.8 to -10.8), library10 - 570 imines and 570 amines (-8.1 to -8.7); we see that DBA derivatives are good potential ligands, at least as compared to the imines and amines of library10. Considering their size, the Ugi products seem better candidates due to the large pocket size for tubulin, see the above image, though their binding affinities are not significantly better considering the size of the libraries docked.