Document Detail

Ligand binding gradually disrupts water network in thrombin: Enthalpic and entropic changes reveal classical hydrophobic effect.
MedLine Citation:
PMID:  22612268     Owner:  NLM     Status:  Publisher    
Well-ordered water molecules are displaced from thrombin's hydrophobic S3/4-pocket by P3-varied ligands (Gly, D-Ala, D-Val, D-Leu to D-Cha with increased hydrophobicity and steric requirement). Two series with 2-(aminomethyl)-5-chlorobenzylamide and 4-amidinobenzylamide at P1 were examined by ITC and crystallography. Though experiencing different interactions in S1, they display almost equal potency. For both scaffolds the terminal benzylsulfonyl substituent differs in binding, whereas the increasingly bulky P3-groups address S3/4 pocket similarly. Small substituents leave solvation pattern unperturbed as found in the uncomplexed enzyme while increasingly larger ones stepwise displace the waters. Medium-sized groups show patterns with partially occupied waters. The overall 40-fold affinity enhancement correlates with water displacement and growing number of van der Waals contacts and is mainly attributed to favorable entropy. Both Gly derivatives deviate from the series and adopt different binding modes. Nonetheless their thermodynamic signatures are virtually identical with the homologous D-Ala derivatives. Accordingly unchanged thermodynamic profiles are no reliable indicator for conserved binding modes.
Adam Biela; Frank Sielaff; Felix Terwesten; Andreas Heine; Torsten Steinmetzer; Gerhard Klebe
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-5-21
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  -     ISSN:  1520-4804     ISO Abbreviation:  -     Publication Date:  2012 May 
Date Detail:
Created Date:  2012-5-22     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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