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Exploring the Subtleties of Drug−Receptor Interactions: The Case of Matrix Metalloproteinases
- Source :
- Journal of the American Chemical Society. 129:2466-2475
- Publication Year :
- 2007
- Publisher :
- American Chemical Society (ACS), 2007.
-
Abstract
- By solving high-resolution crystal structures of a large number (14 in this case) of adducts of matrix metalloproteinase 12 (MMP12) with strong, nanomolar, inhibitors all derived from a single ligand scaffold, it is shown that the energetics of the ligand-protein interactions can be accounted for directly from the structures to a level of detail that allows us to rationalize for the differential binding affinity between pairs of closely related ligands. In each case, variations in binding affinities can be traced back to slight improvements or worsening of specific interactions with the protein of one or more ligand atoms. Isothermal calorimetry measurements show that the binding of this class of MMP inhibitors is largely enthalpy driven, but a favorable entropic contribution is always present. The binding enthalpy of acetohydroxamic acid (AHA), the prototype zinc-binding group in MMP drug discovery, has been also accurately measured. In principle, this research permits the planning of either improved inhibitors, or inhibitors with improved selectivity for one or another MMP. The present analysis is applicable to any drug target for which structural information on adducts with a series of homologous ligands can be obtained, while structural information obtained from in silico docking is probably not accurate enough for this type of study.
- Subjects :
- Stereochemistry
Receptors, Drug
Matrix Metalloproteinase Inhibitors
Hydroxamic Acids
Ligands
Biochemistry
Catalysis
Adduct
Colloid and Surface Chemistry
Matrix Metalloproteinase 12
Matrix Metalloproteinase 13
Hydrolase
medicine
Drug Interactions
Protease Inhibitors
Binding Sites
Chemistry
Drug discovery
Acetohydroxamic acid
Titrimetry
Isothermal titration calorimetry
General Chemistry
Ligand (biochemistry)
Thermodynamics
Drug receptor
Selectivity
medicine.drug
Subjects
Details
- ISSN :
- 15205126 and 00027863
- Volume :
- 129
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....bc3d8e734c42d3fb798cbd6e7aa89529