Document Detail

Application of fragment screening and fragment linking to the discovery of novel thrombin inhibitors.
MedLine Citation:
PMID:  16480269     Owner:  NLM     Status:  MEDLINE    
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.
Nigel Howard; Chris Abell; Wendy Blakemore; Gianni Chessari; Miles Congreve; Steven Howard; Harren Jhoti; Christopher W Murray; Lisa C A Seavers; Rob L M van Montfort
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Feb 
Date Detail:
Created Date:  2006-02-16     Completed Date:  2006-04-10     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1346-55     Citation Subset:  IM    
Astex Therapeutics, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
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MeSH Terms
Carbamates / chemical synthesis,  chemistry
Crystallography, X-Ray
Databases, Factual
Models, Molecular*
Protein Conformation
Structure-Activity Relationship
Sulfonamides / chemical synthesis,  chemistry
Tetrazoles / chemical synthesis,  chemistry
Thrombin / antagonists & inhibitors*,  chemistry*
Reg. No./Substance:
0/Carbamates; 0/Sulfonamides; 0/Tetrazoles; EC

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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