Description
Experimental Technique/Method:X-RAY DIFFRACTION
Resolution:1.66
Classification:HYDROLASE/HYDROLASE INHIBITOR
Release Date:2014-12-10
Deposition Date:2013-06-02
Revision Date:
Molecular Weight:40281.62
Macromolecule Type:Protein
Residue Count:342
Atom Site Count:2793
DOI:10.2210/pdb4l19/pdb
Abstract:
Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans.
Resolution:1.66
Classification:HYDROLASE/HYDROLASE INHIBITOR
Release Date:2014-12-10
Deposition Date:2013-06-02
Revision Date:
Molecular Weight:40281.62
Macromolecule Type:Protein
Residue Count:342
Atom Site Count:2793
DOI:10.2210/pdb4l19/pdb
Abstract:
Matrix metalloproteinase 13 (MMP-13) has been shown to be the main collagenase responsible for degradation of articular cartilage during osteoarthritis and therefore represents a target for drug development. As a result of high-throughput screening and structure-activity relationship studies, we identified a novel, highly selective class of MMP-13 inhibitors (compounds 1 (Q), 2 (Q1), and 3 (Q2)). Mechanistic characterization revealed a noncompetitive nature of these inhibitors with binding constants in the low micromolar range. Crystallographic analyses revealed two binding modes for compound 2 in the MMP-13 S1' subsite and in an S1/S2* subsite. Type II collagen- and cartilage-protective effects exhibited by compounds 1, 2, and 3 suggested that these compounds might be efficacious in future in vivo studies. Finally, these compounds were also highly selective when tested against a panel of 30 proteases, which, in combination with a good CYP inhibition profile, suggested low off-target toxicity and drug-drug interactions in humans.
| Date made available | 2014 |
|---|---|
| Publisher | RCSB-PDB |