PDB 2HU6 deposited: 2006-07-26 modified: 2009-02-24
Title Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor
Authors Calderone, V., Fragai, M., Guarna, A., Machetti, F., Mannino, C., Nievo, M., Papakyriakou, A.
Structure factors resolution 1.32 rfactor 0.16062 rfree 0.18176
DPI 0.15 theoretical min: 0.05

Starting from 3-aza-6,8-dioxa-bicyclo[3.2.1]octane scaffold (BTAa) a virtual library of molecules was generated and screened in silico against the crystal structure of the Human Macrophage Metalloelastase (MMP-12). The molecules obtaining high score were synthesized and the affinity for the catalytic domain of MMP-12 was experimentally proved by NMR experiments. A BTAa scaffold 20 having a N-hydroxyurea group in position 3 and a p-phenylbenzylcarboxy amide in position 7 showed a fair inhibition potency (IC50 = 149 microM) for MMP-12 and some selectivity towards five different MMPs. These results, taken together with the X-ray structure of the adduct between MMP-12, the inhibitor 20 and the acetohydroxamic acid (AHA), suggest that bicyclic scaffold derivatives may be exploited for the design of new selective matrix metalloproteinase inhibitors (MMPIs).

Bioorg.Med.Chem. 2006 Nov; 14(22):7392-7403 doi:10.1016/j.bmc.2006.07.028

Cross References
Database source Identifier Description
PubMed 16899369 BMECEP
Biomolecule Structure Assembly Serial Assembly Type Conformational State Chains Ligands Atoms
2HU6/0 2HU6 0 monomer 0 1 7 1405