3vbx

Publication Abstract from PubMed

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.

Implications of Promiscuous Pim-1 Kinase Fragment Inhibitor Hydrophobic Interactions for Fragment-Based Drug Design.,Good AC, Liu J, Hirth B, Asmussen G, Xiang Y, Biemann HP, Bishop KA, Fremgen T, Fitzgerald M, Gladysheva T, Jain A, Jancsics K, Metz M, Papoulis A, Skerlj R, Stepp JD, Wei RR J Med Chem. 2012 Mar 5. PMID:22339127^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.