1WBW

Identification of novel p38 alpha MAP Kinase inhibitors using fragment-based lead generation.

1WBW の概要

• エントリーDOI: 10.2210/pdb1wbw/pdb
• 関連するPDBエントリー: 1A9U 1BL6 1BL7 1BMK 1DI9 1IAN 1KV1 1KV2 1M7Q 1OUK 1OUY 1OVE 1OZ1 1R39 1R3C 1W7H 1W82 1W83 1W84 1WBN 1WBO 1WBS 1WBT 1WBV 1WFC 1YQJ 1ZZ2 1ZZL
• 分子名称: MITOGEN-ACTIVATED PROTEIN KINASE 14, 3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE (3 entities in total)
• 機能のキーワード: p38, map kinase, inhibitor structure, alternative splicing, atp-binding, nuclear protein, phosphorylation, serine/threonine protein kinase, transferase
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Cytoplasm (By similarity): Q16539
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 41593.49

構造登録者

Tickle, J.,Cleasby, A.,Devine, L.A.,Jhoti, H. (登録日: 2004-11-05, 公開日: 2005-11-03, 最終更新日: 2024-05-08)

主引用文献

Gill, A.,Frederickson, M.,Cleasby, A.,Woodhead, S.J.,Carr, M.G.,Woodhead, A.J.,Walker, M.T.,Congreve, M.S.,Devine, L.A.,Tisi, D.,O'Reilly, M.,Seavers, L.,Davis, D.J.,Curry, J.,Anthony, R.,Padova, A.,Murray, C.W.,Carr, R.A.E.,Jhoti, H.
Identification of Novel P38Alpha Map Kinase Inhibitors Using Fragment-Based Lead Generation
J.Med.Chem., 48:414-, 2005

PubMed Abstract: We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.

PubMed: 15658855
DOI: 10.1021/JM049575N

実験手法

X-RAY DIFFRACTION (2.41 Å)