Druggability of protein–protein interactions
Véronique Hamon, Xavier Morelli · 2013
It appears essential for pharmaceutical and academic research groups to go beyond traditional targets to ‘get pharmaceutical R&D back on track’ [1]. To this end, two challenging sources of improvement are currently being considered: on the one hand, the selection of new relevant targets; and on the other hand, access to chemical libraries adequate for screening campaigns. Among the emerging new alternatives, protein–protein interaction (PPI) modulation is drawing great interest as knowledge grows about cellular protein interaction networks and their role in numerous cell disorders (for more recent information on this topic, see [2]). The human interactome (the complete network of protein interactions in a cell) comprises between 130,000 and 650,000 PPIs and represents a large reservoir for potential new modulator development. Nevertheless, this biological area of transiently formed complexes has long been ignored due to the 3D structural and biophysical complexity of the interfacial features. Therefore, PPIs were historically classified as difficult targets (for a definition and review, see [3]), but their recent top-ranking status as potential sources of innovation in drug discovery leads to questioning of their ‘poorly druggable’ reputation. This chapter will present the recent developments and theories that allow for assessing PPI druggability in silico and the chemical space associated with orthosteric modulators (a subset of this new challenging class of targets).