3VBT
Exploitation of hydrogen bonding constraints and flat hydrophobic energy landscapes in Pim-1 kinase needle screening and inhibitor design
Summary for 3VBT
| Entry DOI | 10.2210/pdb3vbt/pdb |
| Related | 3VBQ 3VBV 3VBW 3VBX 3VBY 3VC4 |
| Descriptor | Serine/threonine-protein kinase pim-1, 4-chloro-2-(1H-pyrazol-3-yl)phenol (3 entities in total) |
| Functional Keywords | pim1, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
| Total number of polymer chains | 1 |
| Total formula weight | 34675.71 |
| Authors | |
| Primary citation | Good, A.C.,Liu, J.,Hirth, B.,Asmussen, G.,Xiang, Y.,Biemann, H.P.,Bishop, K.A.,Fremgen, T.,Fitzgerald, M.,Gladysheva, T.,Jain, A.,Jancsics, K.,Metz, M.,Papoulis, A.,Skerlj, R.,Stepp, J.D.,Wei, R.R. Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design. J.Med.Chem., 55:2641-2648, 2012 Cited by PubMed 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. PubMed: 22339127DOI: 10.1021/jm2014698 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.23 Å) |
Structure validation
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