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Structure-guided identification of 2-arylbenzothiazoles as disruptors of the oncogenic MTDH-SND1 protein-protein

Emadeldin M Kamel1, Sally Mostafa Khadrawy2, Ahmed A Allam2

  • 1Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt.

Archives of Biochemistry and Biophysics
|July 24, 2026
PubMed

Insights

Researchers identified small molecules that disrupt the metadherin (MTDH) and staphylococcal nuclease and tudor domain-containing 1 (SND1) protein-protein interaction (PPI), a key driver of cancer progression. This study validates a computational approach for discovering novel cancer therapeutics targeting MTDH-SND1 PPIs.

Area of Science:

  • Biochemistry
  • Computational Biology
  • Medicinal Chemistry

Background:

  • The protein-protein interaction (PPI) between metadherin (MTDH) and staphylococcal nuclease and tudor domain-containing 1 (SND1) is a critical oncogenic pathway in various cancers.
  • Targeting the MTDH-SND1 interface presents a therapeutic opportunity, yet remains largely underexplored.

Purpose of the Study:

  • To identify small-molecule inhibitors of the MTDH-SND1 PPI using an integrated computational and experimental strategy.
  • To validate 2-arylbenzothiazoles as a promising chemotype for disrupting the MTDH-SND1 interaction.

Main Methods:

  • Screened a library of 4149 2-arylbenzothiazoles using hierarchical docking and MM/PBSA refinement against the MTDH-binding site on SND1.
  • Conducted 1-μs molecular dynamics (MD) simulations for pose stability and interfacial engagement analysis.
  • Validated top candidates using split-luciferase complementation assays, luciferase counterscreens, and microscale thermophoresis (MST).

Main Results:

  • Identified four potent inhibitors (L1-L4) of the MTDH-SND1 PPI with low-micromolar IC50 values in cell-free and cell-based assays.
  • MD simulations and MM/PBSA analyses revealed hydrophobic interactions driving ligand binding within the interfacial groove.
  • MST confirmed direct binding of inhibitors to SND1, with low-micromolar dissociation constants (KD).

Conclusions:

  • 2-Arylbenzothiazoles represent a viable class of compounds for inhibiting the MTDH-SND1 PPI.
  • The developed computational-experimental framework is effective for discovering and optimizing MTDH-SND1-targeting therapeutics.

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