Pocket-based drug design: exploring pocket space

The identification and application of druggable pockets of targets play a key role in in silico drug design, which is a fundamental step in structure-based drug design. Herein, some recent progresses and developments of the computational analysis of pockets have been covered. Also, the pockets at the protein-protein interfaces (PPI) have been considered to further explore the pocket space for drug discovery. We have presented two case studies targeting the kinetic pockets generated by normal mode analysis and molecular dynamics method, respectively, in which we focus upon incorporating the pocket flexibility into the two-dimensional virtual screening with both affinity and specificity. We applied the specificity and affinity (SPA) score to quantitatively estimate affinity and evaluate specificity using the intrinsic specificity ratio (ISR) as a quantitative criterion. In one of two cases, we also included some applications of pockets located at the dimer interfaces to emphasize the role of PPI in drug discovery. This review will attempt to summarize the current status of this pocket issue and will present some prospective avenues of further inquiry.