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Related Experiment Video

Updated: Jun 18, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Structure-Guided Discovery of a Nonpeptidic MT5-MMP Inhibitor.

Antoine Magniez1, Johanna Giovannini1, Pauline Zipfel1

  • 1Université Caen Normandie, Normandie Univ, CERMN UR4258, F-14000 Caen, France.

ACS Medicinal Chemistry Letters
|June 17, 2026
PubMed
Summary

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11<sup>th</sup> National Conference of the French Chemoinformatics Society (SFCi).

Molecular informatics·2026

Researchers identified a novel nonpeptidic compound targeting Membrane type 5-matrix metalloproteinase (MT5-MMP), a key enzyme in Alzheimer's disease pathology. This discovery offers a new avenue for developing Alzheimer's therapeutics.

Area of Science:

  • Biochemistry
  • Neuroscience
  • Medicinal Chemistry

Background:

  • Membrane type 5-matrix metalloproteinase (MT5-MMP, MMP-24) is implicated in amyloid precursor protein processing and Alzheimer's disease.
  • MT5-MMP represents a promising yet underexplored therapeutic target for Alzheimer's disease.

Purpose of the Study:

  • To identify the first nonpeptidic inhibitor for MT5-MMP using a structure-guided drug design approach.
  • To establish a starting point for the optimization of MT5-MMP inhibitors.

Main Methods:

  • Homology modeling of the MT5-MMP catalytic domain based on the MT3-MMP/batimastat structure.
  • Molecular dynamics and ensemble docking applied to a zinc-binding group (ZBG)-focused library.
  • Experimental validation using batimastat and subsequent lead compound optimization.
Keywords:
Alzheimer’s diseaseMT5-MMPmetalloprotease inhibitormolecular dockingzinc-binding groupη-secretase

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Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source
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Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source

Published on: May 29, 2021

Related Experiment Videos

Last Updated: Jun 18, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
10:33

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

Published on: October 26, 2015

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source
08:35

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source

Published on: May 29, 2021

Main Results:

  • A homology model of MT5-MMP was successfully built and validated.
  • A library of 3851 compounds was screened, leading to the identification of a promising scaffold.
  • Compound 17, featuring a hydroxamic acid ZBG, emerged as the first nonpeptidic hit, inhibiting MT5-MMP with an IC50 of 6 μM.

Conclusions:

  • The study presents the first nonpeptidic hit compound for MT5-MMP, a significant advancement in targeting this enzyme.
  • The identified scaffold provides a basis for future medicinal chemistry efforts to develop potent MT5-MMP inhibitors for Alzheimer's disease treatment.