Predicting druggable binding sites at the protein–protein interface

Small-Molecule Inhibitors of IL-2/IL-2R: Lessons Learned and Applied

“…Due to their high value and detailed structural characterization, Bcl-xL, MDM2, and IL-2 have all been used for successful validation of virtual screening methods (Betzi et al 2009;Sperandio et al 2010;Casey et al 2009;Fuller et al 2009;Helms 2007, 2009;Enyedy et al 2001;Bowman et al 2007;Mukherjee et al 2010). Bcl-xL and MDM2, in particular, have attracted special attention for in silico screening against molecules in existing chemical libraries.…”

“…The topology of inhibitors has emerged as one of the strongest themes from PPI inhibitor discovery, with linear I-and L-shaped structures or branched E-, X-, and T-shaped molecules being common Fuller et al 2009;Reynes et al 2010). These multipronged scaffolds are consistent with binding to several smaller subsites found on PPI.…”

“…Other small molecules make similar use of grooves and dynamic regions at the junction of two structural elements (Laskowski et al 1996;Glaser et al 2006). In the literature, most small-molecule inhibitors of PPIs target interfaces that are comprised of short linear peptide sequences or helical motifs (Wells and McClendon 2007;Fuller et al 2009). Peptide-binding surfaces might be inherently more druggable than other PPI because they are more concave or smaller, or because small-molecule scaffolds can be designed to mimic the periodic display of peptide side chains.…”

“…LE might be particularly low for PPI surfaces because they have relatively few of the combined chemical (such as buried salt bridges) and physical features (cavities) necessary for the highest affinity interactions (Wells and McClendon 2007). Similarly, the observation that PPI contain multiple, small subsites suggests that larger compounds will be needed to link fragments across these sites (Fuller et al 2009). …”

“…Active fragments are then linked or evolved in a second step and retested for binding or inhibition of the target. Fragment-based approaches might be especially suitable for PPI because they favor binding sites with multiple and nearby subsites, which appears to be the trend for PPI/smallmolecule systems (Fuller et al 2009). The sophistication of fragment linking and growing also potentially enables the assembly of small molecules that explore and capture available surface features for high-affinity binding.…”