TIES. We use the TIES to predict free energy differences for two groups of compound pairs, using compounds L30 and L2 as the reference structures. The two compounds differ by an isopropyl group which extends into a hydrophobic binding pocket (Figure ). TIES20 is used to identify the maximum common substructure and to generate the topology and coordinate files for the hybrid compounds. A total of 103 compound pairs have been constructed using the two reference compounds. The compound pairs are chosen so that the atoms in the reference compounds are largely in the common region, with no more than 5 atoms in the alchemical region.