1a85 Citations

Structure of malonic acid-based inhibitors bound to human neutrophil collagenase. A new binding mode explains apparently anomalous data.

Protein Sci. 7 1303-9 (1998)
Cited: 13 times
EuropePMC logo PMID: 9655333

Abstract

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases, which have been implicated in various disease processes. Various classes of MMP inhibitors, including hydroxamic acids, phosphinic acids, and thiols, have been previously described. Most of these mimic peptides, and most likely bind analogous to the corresponding peptide substrates. Among the hydroxamic acids, malonic acid derivatives have been used as MMP inhibitors, although optimization of their inhibition potency was not successful. Here we report the design of malonic acid-based inhibitors using the X-ray structure of a collagenase/inhibitor complex, which revealed a nonsubstrate-like binding mode. The proposed beta-type turn-like conformation for the improved inhibitors was confirmed by X-ray crystallography. The observation of nonsubstrate-like binding confirms the original strategy for structure-based modeling of improved malonic acid inhibitors, and explains kinetic data that are inconsistent with substrate-like binding. Detailed interactions for the improved inhibitors seen in the crystal structure also suggest possibilities for further modifications in cycles of structure based drug design. Indeed, we have designed nonpeptidic inhibitors with approximately 500-fold improved inhibition based on these structures.

Articles - 1a85 mentioned but not cited (2)

  1. A comparison of the binding sites of matrix metalloproteinases and tumor necrosis factor-alpha converting enzyme: implications for selectivity. Lukacova V, Zhang Y, Kroll DM, Raha S, Comez D, Balaz S. J. Med. Chem. 48 2361-2370 (2005)
  2. Coupling protein engineering with probe design to inhibit and image matrix metalloproteinases with controlled specificity. Morell M, Nguyen Duc T, Willis AL, Syed S, Lee J, Deu E, Deng Y, Xiao J, Turk BE, Jessen JR, Weiss SJ, Bogyo M. J. Am. Chem. Soc. 135 9139-9148 (2013)


Reviews citing this publication (2)

  1. Future challenges facing the development of specific active-site-directed synthetic inhibitors of MMPs. Cuniasse P, Devel L, Makaritis A, Beau F, Georgiadis D, Matziari M, Yiotakis A, Dive V. Biochimie 87 393-402 (2005)
  2. The proteolytic environment of chronic wounds. Yager DR, Nwomeh BC. Wound Repair Regen 7 433-441 (1999)

Articles citing this publication (9)

  1. Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12. Morales R, Perrier S, Florent JM, Beltra J, Dufour S, De Mendez I, Manceau P, Tertre A, Moreau F, Compere D, Dublanchet AC, O'Gara M. J. Mol. Biol. 341 1063-1076 (2004)
  2. Docking studies of matrix metalloproteinase inhibitors: zinc parameter optimization to improve the binding free energy prediction. Hu X, Shelver WH. J. Mol. Graph. Model. 22 115-126 (2003)
  3. A practical approach to docking of zinc metalloproteinase inhibitors. Hu X, Balaz S, Shelver WH. J. Mol. Graph. Model. 22 293-307 (2004)
  4. Prediction of interaction mode between a typical ACE inhibitor and MMP-9 active site. Yamamoto D, Takai S, Miyazaki M. Biochem. Biophys. Res. Commun. 354 981-984 (2007)
  5. Protease inhibitors - part 5. Alkyl/arylsulfonyl- and arylsulfonylureido-/arylureido- glycine hydroxamate inhibitors of Clostridium histolyticum collagenase. Scozzafava A, Supuran CT. Eur J Med Chem 35 299-307 (2000)
  6. Protease inhibitors. Part 8: synthesis of potent Clostridium histolyticum collagenase inhibitors incorporating sulfonylated L-alanine hydroxamate moieties. Scozzafava A, Supuran CT. Bioorg. Med. Chem. 8 637-645 (2000)
  7. Calcium regulates tertiary structure and enzymatic activity of human endometase/matrilysin-2 and its role in promoting human breast cancer cell invasion. Lee S, Park HI, Sang QX. Biochem. J. 403 31-42 (2007)
  8. Protease inhibitors: Synthesis of L-alanine hydroxamate sulfonylated derivatives as inhibitors of clostridium histolyticum collagenase. Supuran CT, Briganti F, Mincione G, Scozzafava A. J. Enzym. Inhib. 15 111-128 (2000)
  9. Peptide models XLV: conformational properties of N-formyl-L-methioninamide and its relevance to methionine in proteins. Láng A, Csizmadia IG, Perczel A. Proteins 58 571-588 (2005)