Ligand binding stepwise disrupts water network in thrombin: Enthalpic and entropic changes reveal classical hydrophobic effect
| Autor: | A. Biela, Felix Terwesten, Torsten Steinmetzer, Gerhard Klebe, Frank Sielaff, Andreas Heine |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Steric effects
Benzylamines Proline Stereochemistry Substituent Amidines Molecular Conformation Calorimetry Molecular Dynamics Simulation Crystallography X-Ray Ligands 01 natural sciences Hydrophobic effect 03 medical and health sciences chemistry.chemical_compound symbols.namesake Thrombin Drug Discovery Benzyl Compounds medicine Molecule Humans Amino Acids 030304 developmental biology 0303 health sciences Sulfonamides Binding Sites 010405 organic chemistry Solvation Fibrinogen Water Hydrogen Bonding Stereoisomerism 0104 chemical sciences chemistry Drug Design symbols Molecular Medicine Thermodynamics Peptidomimetics van der Waals force Hydrophobic and Hydrophilic Interactions medicine.drug Entropy (order and disorder) Protein Binding |
| Zdroj: | J. Med. Chem., 55 (2012) 6094-6110. |
| Popis: | 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. Although 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 the 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|