Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design
| Autor: | Tatiana Gladysheva, Yibin Xiang, A.C Good, Bradford H. Hirth, T Fremgen, Gary Asmussen, Renato Skerlj, A Jain, Kimberly Bishop, J.D Stepp, Ronnie Wei, Katherine Jancsics, Maria Fitzgerald, Jinyu Liu, H.P Biemann, Markus Metz, Andrew T Papoulis |
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| Rok vydání: | 2012 |
| Předmět: |
Steric effects
Models Molecular Molecular Structure Chemistry Stereochemistry Hydrogen bond Stereoisomerism Plasma protein binding Crystallography X-Ray Hydrophobic effect Crystallography Structure-Activity Relationship Proto-Oncogene Proteins c-pim-1 Docking (molecular) Drug Design Drug Discovery Molecular Medicine Structure–activity relationship Molecule Surface plasmon resonance Enzyme Inhibitors Hydrophobic and Hydrophilic Interactions Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 55(6) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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