4QP7: Crystal Structure Of Erk2 In Complex With 2-(1h-pyrazol-4-yl)-5h- Pyrrolo[2,3-b]pyrazine

Citation:
Abstract
A fragment-based lead discovery approach was used to discover novel ERK2 inhibitors. The crystal structure of N-benzyl-9H-purin-6-amine 1 in complex with ERK2 elucidated its hinge-binding mode. In addition, the simultaneous binding of an imidazole molecule adjacent to 1 suggested a direction for fragment expansion. Structure-based core hopping applied to 1 led to 5H-pyrrolo[3,2-b]pyrazine (3) that afforded direct vectors to probe the pockets of interest while retaining the essential hinge binding elements. Utilizing the new vectors for SAR exploration, the new core 3 was quickly optimized to compound 39 resulting in a greater than 6600-fold improvement in potency.
PDB ID: 4QP7Download
MMDB ID: 132768
PDB Deposition Date: 2014/6/22
Updated in MMDB: 2015/12
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
Similar Structures:
Biological Unit for 4QP7: monomeric; determined by author and by software (PISA)
Molecular Components in 4QP7
Label Count Molecule
Protein (1 molecule)
1
Mitogen-activated Protein Kinase 1(Gene symbol: MAPK1)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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