We have studied the subtleties of fragment docking and binding using data 
generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data 
analyses have been undertaken using inhibitor complexes derived from an in-house 
surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a 
de novo designed fragment inhibitor hybrid. These investigations highlight that 
fragments that do not fill their binding pocket can exhibit promiscuous 
hydrophobic interactions due to the lack of steric constraints imposed on them 
by the boundaries of said pocket. As a result, docking modes that disagree with 
an observed crystal structure but maintain key crystallographically observed 
hydrogen bonds still have potential value in ligand design and optimization. 
This observation runs counter to the lore in fragment-based drug design that all 
fragment elaboration must be based on the parent crystal structure alone.