3VBT: Exploitation Of Hydrogen Bonding Constraints And Flat Hydrophobic Energy Landscapes In Pim-1 Kinase Needle Screening And Inhibitor Design

Citation:
Abstract
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.
PDB ID: 3VBTDownload
MMDB ID: 98201
PDB Deposition Date: 2012/1/2
Updated in MMDB: 2012/05
Experimental Method:
x-ray diffraction
Resolution: 2.23  Å
Source Organism:
Similar Structures:
Biological Unit for 3VBT: monomeric; determined by author and by software (PISA)
Molecular Components in 3VBT
Label Count Molecule
Protein (1 molecule)
1
Serine/threonine-protein Kinase Pim-1(Gene symbol: PIM1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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