Structure-Guided Discovery of a Nonpeptidic MT5-MMP Inhibitor

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.