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.
Abstract:
Membrane type 5-matrix metalloproteinase (MT5-MMP, MMP-24), an η-secretase involved in amyloid precursor protein processing, is a promising but unexplored target in Alzheimer's disease. We report here the identification of a first nonpeptidic hit for MT5-MMP through a structure-guided approach. A homology model of the MT5-MMP catalytic domain was built from the MT3-MMP/batimastat structure and validated by both docking and experimental inhibition data obtained with batimastat (IC50 = 3 nM). To account for binding-site plasticity, especially that of the S1' pocket, molecular dynamics and ensemble docking were applied to a zinc-binding group (ZBG)-focused library of 3851 compounds. Although the initial screening campaign yielded only weakly active candidates, analysis of docking poses identified a relevant scaffold for optimization. Replacement of a carboxylic acid ZBG by a hydroxamic acid led to compound 17, which inhibited MT5-MMP with an IC50 of 6 μM and established a first nonpeptidic hit for future optimization.
Insights
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.
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.
