As the scaffold shares a core with the inhibitor from the 4D09 crystal structure 18 , 4D09 coordinates were used as a reference for the generation of binding poses for each ligand in the library. Coordinates of the largest substructure matches between each ligand and the reference were constrained to the same coordinates as in the crystal structure. For the re-maining atoms initial guesses were assigned via constrained embedding following the ETKDG algorithm as implemented in RDKit . This approach was not always able to respect the constrained positions of the common substructures and would return a different outcome depending on the initial random seed. A hundred of such structures were constructed for each ligand and the one with a smallest RMSD to the reference was selected.