 |
PDBsum entry 1wbv
|
|
|
|
References listed in PDB file
|
 |
|
Key reference
|
|
|
Title
|
|
Identification of novel p38alpha map kinase inhibitors using fragment-Based lead generation.
|
|
|
Authors
|
|
A.L.Gill,
M.Frederickson,
A.Cleasby,
S.J.Woodhead,
M.G.Carr,
A.J.Woodhead,
M.T.Walker,
M.S.Congreve,
L.A.Devine,
D.Tisi,
M.O'Reilly,
L.C.Seavers,
D.J.Davis,
J.Curry,
R.Anthony,
A.Padova,
C.W.Murray,
R.A.Carr,
H.Jhoti.
|
|
|
Ref.
|
|
J Med Chem, 2005,
48,
414-426.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
