Protein-Protein Interaction Inhibition (2P2I): Fewer and Fewer Undruggable Targets

Low molecular weight inhibitors of Protein-Protein Interactions (PPI's) have been identified for a number of different systems indicating the viability of the computer-aided drug design approaches. However, pathways undertaken by researchers in pharmaceutical companies or in academic laboratories are not always clearly defined and the protocols that allow the identification of lead compounds often remain blurry. We will enumerate in this review the main approaches carried out to identify and validate PPI's inhibitors. Emphasis will be placed, in a first part, on issues of particular significance to PPI's such as the problem of identification and validation of interacting sites and on the methods that allow assessing the 3D structure of a targeted complex. On the second part of this review, we will define approaches that allow a rapid identification of hits capable of inhibiting PPI's. We will highlight the problem of the scoring functions and demonstrate that the majority of the functions available to researchers are not especially relevant for PPI's. We will define why consensus scoring can be an alternative and we will propose GFscore, a non linear ranked-by number consensus scoring function as a solution to this problem. We will finally discuss the actual challenges that still remain, particularly the problem of the treatment of the receptor flexibility and of the water molecules at the interface of the Protein-Protein complexes.