1W84

p38 Kinase crystal structure in complex with small molecule inhibitor

Summary for 1W84

• Entry DOI: 10.2210/pdb1w84/pdb
• Related: 1A9U 1BL6 1BL7 1BMK 1DI9 1IAN 1KV1 1KV2 1M7Q 1OUK 1OUY 1OVE 1OZ1 1R39 1R3C 1W7H 1W83 1W84 1WFC
• Descriptor: MITOGEN-ACTIVATED PROTEIN KINASE 14, 3-(2-PYRIDIN-4-YLETHYL)-1H-INDOLE (3 entities in total)
• Functional Keywords: kinase/inhibitor, kinase-inhibitor complex, p38, kinase, inhibitor complex
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 41565.48

Authors

Tickle, J.,Jhoti, H.,Cleasby, A.,Devine, L. (deposition date: 2004-09-16, release date: 2005-02-08, Last modification date: 2024-05-08)

Primary citation

Gill, A.L.,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.C.,Davis, D.J.,Curry, J.,Anthony, R.,Padova, A.,Murray, C.W.,Carr, R.A.,Jhoti, H.
Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.
J. Med. Chem., 48:414-426, 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

Experimental method

X-RAY DIFFRACTION (2.2 Å)