Consensus Strategies for Challenging Dockings

The attention toward protein-protein interactions as potential targets for the design of very specific drugs dramatically increased during the last few years. The binding regions involved in protein-protein interactions are rarely deep and well-defined cavities, as found in the active site of an enzyme, but are often characterized by solvent-exposed clefts on the protein surface. This feature makes the definition of a reliable docking protocol quite challenging. This workshop will be focused upon the development of a docking protocol for the identification of small organic molecules potentially able to interfere with the interaction of two target proteins (hereafter referred as proteins A and B). The study will cover two possible scenarios: 1) The crystal structure of the AB complex is available; 2) The structure of either A or B is available co-crystallized with a known inhibitor. In both scenarios we will analyze the complex, finding and fixing all possible sources of error and preparing the model for docking experiments (fixing missing residues, assigning the correct protonation state, relaxing the structure through short molecular dynamic runs followed by geometry minimizations). A docking protocol will then be realized and tested through the docking of small databases of compounds with known activity. The results of both scenarios will be compared and discussed. As consensus between different computational methods might be a key to improve the success rate of a virtual screening procedure, an alternative docking protocol will be also realized by using a different method and software. The two protocols will be tested within a virtual screening case study and those hits identified by each single protocol will be compared to those identified by both protocols applied on a consensus basis.