PDB 3N2U deposited: 2010-05-19 modified: 2010-12-08
Title Crystal structure of the catalytic domain of human MMP12 complexed with the inhibitor N-hydroxy-2-(4-methoxy-N(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)ethyl)phenylsulfonamido)acetamide
Authors Attolino, E., Calderone, V., Dragoni, E., Fragai, M., Luchinat, C., Nativi, C., Richichi, B.
Structure factors resolution 1.81 rfactor 0.16079 rfree 0.21899
DPI 0.43 theoretical min: 0.14
Related PDB Entries 3F15 3F16 3F17 3F18 3F19 3F1A 3LK8 3N2V 3NX7 3RTS 3RTT 4GUY

N-arylsulfonyl-based MMPs inhibitors (MMPIs) are among the most prominent inhibitors possessing nanomolar affinity. However, their poor bioavailability remains critical for the drug development of this family of molecules. The structural analysis of the complex of NNGH (the most representative member of the family) with MMP-12 provided us with the basis to effectively design simple NNGH analogues with enhanced solubility in water. Following this approach, the sec-butyl residue, not directly involved in the binding with MMP, has been replaced with hydrophilic residues thus yielding new potent inhibitors soluble in water.

Eur.J.Med.Chem. 2010 Dec; 45(12):5919-5925 doi:10.1016/j.ejmech.2010.09.057

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.

J.Am.Chem.Soc. 2007 Mar; 129(9):2466-2475 doi:10.1021/ja065156z

Cross References
Database source Identifier Description
ChEMBL Document CHEMBL1629518
PubMed 20965620 EJMCA5
PubMed 17269766 JACSAT
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
3N2U/0 3N2U 0 monomer 0 1 6 1299