3VBT
Exploitation of hydrogen bonding constraints and flat hydrophobic energy landscapes in Pim-1 kinase needle screening and inhibitor design
3VBT の概要
エントリーDOI | 10.2210/pdb3vbt/pdb |
関連するPDBエントリー | 3VBQ 3VBV 3VBW 3VBX 3VBY 3VC4 |
分子名称 | Serine/threonine-protein kinase pim-1, 4-chloro-2-(1H-pyrazol-3-yl)phenol (3 entities in total) |
機能のキーワード | pim1, transferase-transferase inhibitor complex, transferase/transferase inhibitor |
由来する生物種 | Homo sapiens (human) |
細胞内の位置 | Isoform 2: Cytoplasm. Isoform 1: Cell membrane: P11309 |
タンパク質・核酸の鎖数 | 1 |
化学式量合計 | 34675.71 |
構造登録者 | |
主引用文献 | 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 主引用文献が同じPDBエントリー |
実験手法 | X-RAY DIFFRACTION (2.23 Å) |
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