1WBW
Identification of novel p38 alpha MAP Kinase inhibitors using fragment-based lead generation.
Summary for 1WBW
| Entry DOI | 10.2210/pdb1wbw/pdb |
| Related | 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 |
| Descriptor | MITOGEN-ACTIVATED PROTEIN KINASE 14, 3-(1-NAPHTHYLMETHOXY)PYRIDIN-2-AMINE (3 entities in total) |
| Functional Keywords | p38, map kinase, inhibitor structure, alternative splicing, atp-binding, nuclear protein, phosphorylation, serine/threonine protein kinase, transferase |
| Biological source | HOMO SAPIENS (HUMAN) |
| Cellular location | Cytoplasm (By similarity): Q16539 |
| Total number of polymer chains | 1 |
| Total formula weight | 41593.49 |
| Authors | Tickle, J.,Cleasby, A.,Devine, L.A.,Jhoti, H. (deposition date: 2004-11-05, release date: 2005-11-03, Last modification date: 2024-05-08) |
| Primary citation | 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 Cited by 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: 15658855DOI: 10.1021/JM049575N PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.41 Å) |
Structure validation
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