1WBV: Identification Of Novel P38 Alpha Map Kinase Inhibitors Using Fragment-Based Lead Generation

Citation:
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.
PDB ID: 1WBVDownload
MMDB ID: 35852
PDB Deposition Date: 2004/11/5
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 1WBV: monomeric; determined by author and by software (PQS)
Molecular Components in 1WBV
Label Count Molecule
Protein (1 molecule)
1
Mitogen-activated Protein Kinase 14(Gene symbol: MAPK14)
Molecule annotation
Chemicals (5 molecules)
1
1
2
3
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
.