BIOS is based upon two concepts previously developed by the Waldmann group. The scaffolds of natural products can be mapped in a hierarchical manner to create a scaffold tree, a “structural classification of natural products” (SCONP).(170, 171) This allows for logical pathways for the structural simplification of scaffolds. In the second concept, “protein structure similarity clustering” (PSSC), proteins are clustered by three-dimensional shape around the ligand-binding sites, regardless of sequence similarity.(172-174) Merging these two concepts led to the BIOS approach.(156) The ligand of any member of a PSSC could be expected to exhibit some degree of complementarity toward other members of the PSSC and, thus, serve as a starting point for the development of modulators of the other members.