Compound 9(University of Athens)

A streamlined synthetic route was developed to diversify serine-derived phosphinic peptides at the P1 position into dehydroalanine and thio-substituted (cysteine-like) analogues designed to engage the elongated S1 pocket of MMP-13. Three inhibitors (9, 10a, and 10b) were synthesized and evaluated against MMP-13. Compounds 9 and 10a showed high-nanomolar inhibition (K_i = 50 nM and 40 nM, respectively), while the naphthyl analogue 10b was less active (K_i = 100 nM). Compound 10a was the most potent within this series, although the reference inhibitor RXP03 remains more potent (K_i = 16 nM). Molecular docking reproduced the crystallographic pose of a co-crystallized ligand (RMSD = 1.24 Å) and indicated binding features consistent with phosphinate-Zn²⁺ coordination, hydrogen-bonding, and hydrophobic contacts in the S1 pocket. Molecular dynamics simulations further supported stable protein-ligand complexes and provided comparative interaction/stability trends among the three inhibitors. SwissADME predictions indicated high polarity and multiple drug-likeness violations, suggesting limited oral absorption and motivating future optimization (e.g., prodrug/delivery strategies). Selectivity against other MMPs was not assessed in this study.