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PDBsum entry 2zhq
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Hydrolase/hydrolase inhibitor
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PDB id
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2zhq
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References listed in PDB file
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Key reference
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Title
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Non-Additivity of functional group contributions in protein-Ligand binding: a comprehensive study by crystallography and isothermal titration calorimetry.
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Authors
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B.Baum,
L.Muley,
M.Smolinski,
A.Heine,
D.Hangauer,
G.Klebe.
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Ref.
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J Mol Biol, 2010,
397,
1042-1054.
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PubMed id
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Abstract
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Additivity of functional group contributions to protein-ligand binding is a very
popular concept in medicinal chemistry as the basis of rational design and
optimized lead structures. Most of the currently applied scoring functions for
docking build on such additivity models. Even though the limitation of this
concept is well known, case studies examining in detail why additivity fails at
the molecular level are still very scarce. The present study shows, by use of
crystal structure analysis and isothermal titration calorimetry for a congeneric
series of thrombin inhibitors, that extensive cooperative effects between
hydrophobic contacts and hydrogen bond formation are intimately coupled via
dynamic properties of the formed complexes. The formation of optimal lipophilic
contacts with the surface of the thrombin S3 pocket and the full desolvation of
this pocket can conflict with the formation of an optimal hydrogen bond between
ligand and protein. The mutual contributions of the competing interactions
depend on the size of the ligand hydrophobic substituent and influence the
residual mobility of ligand portions at the binding site. Analysis of the
individual crystal structures and factorizing the free energy into enthalpy and
entropy demonstrates that binding affinity of the ligands results from a mixture
of enthalpic contributions from hydrogen bonding and hydrophobic contacts, and
entropic considerations involving an increasing loss of residual mobility of the
bound ligands. This complex picture of mutually competing and partially
compensating enthalpic and entropic effects determines the non-additivity of
free energy contributions to ligand binding at the molecular level.
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