PDBsum entry 2c8z

Hydrolase/hydrolase inhibitor

PDB id: 2c8z

Contents

Protein chains

29 a.a.

251 a.a.

11 a.a.

Ligands

DMS

C2A

Metals

_NA

Waters ×327

References listed in PDB file

Key reference

• Title: Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors.
• Authors: N.Howard, C.Abell, W.Blakemore, G.Chessari, M.Congreve, S.Howard, H.Jhoti, C.W.Murray, L.C.Seavers, R.L.Van montfort.
• Ref.: J Med Chem, 2006, 49, 1346-1355. [DOI no: 10.1021/jm050850v]
• PubMed id: 16480269

Abstract

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.