1 research outputs found
Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design
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