2. Academic Validation
  3. Novel serine-derived Phosphinic peptides as potent MMP-13 inhibitors

Novel serine-derived Phosphinic peptides as potent MMP-13 inhibitors

  • Bioorg Chem. 2026 Jun 5:173:109572. doi: 10.1016/j.bioorg.2026.109572.
Andreas Mores 1,  Moaz M Abdou 2,  Yuxin Xie 3,  Ruba Kellow 4,  Rehab H Abd El-Aleam 5,  Palmer Sivoko Imbenzi 4,  Faez Iqbal Khan 6,  Magdalini Matziari 7
Affiliations

Affiliations

  • 1 Department of Chemistry, Laboratory of Organic Chemistry, University of Athens, Panepistimiopolis, Zografou, 15771 Athens, Greece.
  • 2 Egyptian Petroleum Research Institute, Nasr City, Cairo 11727, Egypt.
  • 3 Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai road, SIP, Suzhou, Jiangsu Province 215123, PR China.
  • 4 Department of Chemistry and Materials Science, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai Road, SIP, Suzhou, Jiangsu Province 215123, PR China.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, MTI, Cairo 11571, Egypt.
  • 6 Department of Biosciences and Bioinformatics, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai road, SIP, Suzhou, Jiangsu Province 215123, PR China. Electronic address: Faez.Khan@xjtlu.edu.cn.
  • 7 Department of Chemistry and Materials Science, School of Science, Xi'an Jiaotong-Liverpool University, 111 Ren'ai Road, SIP, Suzhou, Jiangsu Province 215123, PR China. Electronic address: Magdalini.Matziari@xjtlu.edu.cn.
PMID: 41671738 DOI: 10.1016/j.bioorg.2026.109572
Abstract

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 (Ki = 50 nM and 40 nM, respectively), while the naphthyl analogue 10b was less active (Ki = 100 nM). Compound 10a was the most potent within this series, although the reference inhibitor RXP03 remains more potent (Ki = 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.

Keywords

ADME prediction; Cysteine analogues; Dehydroalanine; MMP-13 inhibitors; Molecular docking; Molecular dynamics; Phosphinic peptides; Serine analogues.

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