Protein-Protein interactions provide a large opportunity space for potential targets due to their unique mode of transforming cellular signaling that leads to important biological functions. It is well documented that the protein-protein interaction surface is too large to be effectively target and disrupt by a small molecule entities. This leads to low potency of the small molecules due to their weak interactions and widely spaced. However a recent developments have clearly demonstrated the drugability of these difficult targets by small molecules with available structural and biochemical information.

Here we present the protein structure and ligand binding information by understanding the buried surface of protein-protein contacts, hot spots, key residues, hydrophobic and polar interactions which are critical for targeting the protein-protein interactions. Also various concepts in lead identification and optimization such as ligand, surface-binding, liphophilic efficiency, predicting metabolism and hepatic stability based on the target class will be presented. Application of design concepts and impact of in-silico approaches will be discussed.