2HU6

Crystal structure of human MMP-12 in complex with acetohydroxamic acid and a bicyclic inhibitor

Summary for 2HU6

• Entry DOI: 10.2210/pdb2hu6/pdb
• Related: 1RMZ 1Y93
• Descriptor: Macrophage metalloelastase, ZINC ION, CALCIUM ION, ... (6 entities in total)
• Functional Keywords: mmp-12, matrix metalloproteinase, macrophage metalloelastase, inhibitor, hydroxamic acid, drug design, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P39900
• Total number of polymer chains: 1
• Total formula weight: 18325.19

Authors

Mannino, C.,Nievo, M.,Machetti, F.,Papakyriakou, A.,Calderone, V.,Fragai, M.,Guarna, A. (deposition date: 2006-07-26, release date: 2006-12-19, Last modification date: 2023-08-30)

Primary citation

Mannino, C.,Nievo, M.,Machetti, F.,Papakyriakou, A.,Calderone, V.,Fragai, M.,Guarna, A.
Synthesis of bicyclic molecular scaffolds (BTAa): an investigation towards new selective MMP-12 inhibitors.
Bioorg.Med.Chem., 14:7392-7403, 2006

PubMed Abstract: 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).

PubMed: 16899369
DOI: 10.1016/j.bmc.2006.07.028

Experimental method

X-RAY DIFFRACTION (1.32 Å)