- Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors
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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.
- Howard, Nigel,Abell, Chris,Blakemore, Wendy,Chessari, Gianni,Congreve, Miles,Howard, Steven,Jhoti, Harren,Murray, Christopher W.,Seavers, Lisa C. A.,Van Montfort, Rob L. M.
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p. 1346 - 1355
(2007/10/03)
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