2C8Y: Thrombin Inhibitors

The screening of fragments is an alternative approach to high-throughput screening for the identification of leads for therapeutic targets. Fragment hits have been discovered using X-ray crystallographic screening of protein crystals of the serine protease enzyme thrombin. The fragment library was designed to avoid any well-precedented, strongly basic functionality. Screening hits included a novel ligand (3), which binds exclusively to the S2-S4 pocket, in addition to smaller fragments which bind to the S1 pocket. The structure of these protein-ligand complexes are presented. A chemistry strategy to link two such fragments together and to synthesize larger drug-sized compounds resulted in the efficient identification of hybrid inhibitors with nanomolar potency (e.g., 7, IC50 = 3.7 nM). These potent ligands occupy the same area of the active site as previously described peptidic inhibitors, while having very different chemical architecture.
PDB ID: 2C8YDownload
MMDB ID: 40286
PDB Deposition Date: 2005/12/8
Updated in MMDB: 2011/10
Experimental Method:
x-ray diffraction
Resolution: 2.2  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 2C8Y: trimeric; determined by author and by software (PQS)
Molecular Components in 2C8Y
Label Count Molecule
Proteins (3 molecules)
Thrombin Light Chain(Gene symbol: F2)
Molecule annotation
Thrombin Heavy Chain(Gene symbol: F2)
Molecule annotation
Hirudin Variant-2
Molecule annotation
Chemicals (5 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB