Exploring the Subtleties of Drug−Receptor Interactions: The Case of Matrix Metalloproteinases
- 2 February 2007
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 129 (9), 2466-2475
- https://doi.org/10.1021/ja065156z
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.Keywords
This publication has 31 references indexed in Scilit:
- Recent advances in MMP inhibitor designCancer and Metastasis Reviews, 2006
- Fragonomics: fragment-based drug discoveryCurrent Opinion in Chemical Biology, 2005
- Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40Nature, 2003
- Crystal Structure of Human MMP9 in Complex with a Reverse Hydroxamate InhibitorJournal of Molecular Biology, 2002
- Matrix Metalloproteinase Inhibitors and Cancer—Trials and TribulationsScience, 2002
- Substrate specificity determinants of human macrophage elastase (MMP-12) based on the 1.1 Å crystal structureJournal of Molecular Biology, 2001
- Stromelysin Inhibitors Designed from Weakly Bound Fragments: Effects of Linking and CooperativityJournal of the American Chemical Society, 1997
- Crystal structures of matrilysin-inhibitor complexesBiochemistry, 1995
- A visual protein crystallographic software system for X11/XviewJournal of Molecular Graphics, 1992
- The detection of sub-units within the crystallographic asymmetric unitActa Crystallographica, 1962