5UWL

Matrix metalloproteinase-13 complexed with selective inhibitor compound (S)-17a

Summary for 5UWL

• Entry DOI: 10.2210/pdb5uwl/pdb
• Related: 5UWK 5UWM 5UWN
• Descriptor: Collagenase 3, ZINC ION, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: metalloproteinase, collagenase, mmp-13, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted, extracellular space, extracellular matrix : P45452
• Total number of polymer chains: 2
• Total formula weight: 40090.93

Authors

Taylor, A.B.,Cao, X.,Hart, P.J. (deposition date: 2017-02-21, release date: 2017-07-12, Last modification date: 2023-10-04)

Primary citation

Choi, J.Y.,Fuerst, R.,Knapinska, A.M.,Taylor, A.B.,Smith, L.,Cao, X.,Hart, P.J.,Fields, G.B.,Roush, W.R.
Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.
J. Med. Chem., 60:5816-5825, 2017

PubMed Abstract: We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn chelating unit was replaced with nonchelating polar residues that bridged over the Zn binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

PubMed: 28653849
DOI: 10.1021/acs.jmedchem.7b00514

Experimental method

X-RAY DIFFRACTION (2.55 Å)