DKK-1 Inhibitors library
3 010 compounds
We used both docking and ligand-based approaches to assemble this subset. Specifically, the DKK1/LRP6 protein-protein interaction (PPI) interface was utilized to select matching ligands from our selection of drug-like compounds (2 709 985 total available molecules). For the docking approach we took into consideration data on analogues of NCI8642, a reported DKK-1/LRP6 interaction inhibitor. Specifically, we focused our design on topological and charge distribution features of the critical Dkk-1 loop that binds to LRP6. We reasoned that blocking/destabilizing this loop feature of the DKK-1/LRP6 PPI may yield modulators and/or activators of Wnt signaling while maintaining ‘normal’ Wnt-Fz-LRP6 signaling.
Fig. 1.Binding interface between LRP6 protein and representative ligand from the focused subset.
For the ligand-based approach we used known DKK-1 inhibitor WAY 262611.
Total library size is 3 014 lead-like compounds.
Fig. 2.(a) Pharmacophore model based on WAY-316606; orange – aromatic/heteroaromatic groups, green-hydrophobic pharmacophore (halogen, CF 3, CHF 2, Me, Et, iPr etc.), blue-positively charged moiety ( +NH 3Alk, +NH 2Alk 2, +NHAlk 3etc.); (b) Superposition of WAY-316606 and our pharmacophore construct used in (sub)library design.