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<p>The metadherin (MTDH)-staphylococcal nuclease and tudor domain containing 1 (SND1) protein-protein interaction is a validated oncogenic driver implicated in cancer cell survival, metastasis, and immune evasion, making it an attractive therapeutic target. In the present study, we applied an integrated in silico-in vitro workflow to identify novel small-molecule disruptors of the MTDH-SND1 interaction from a focused library of 824 1&#xa0;H-pyrrolo[2,3-b]pyridine-3-sulfonamides. Following diversity, purchasability, and drug-likeness filtering, the library was screened by molecular docking against the MTDH-binding region of SND1, and the top candidates were refined by short molecular dynamics (MD) simulations and MM/PBSA rescoring. Five compounds (C1-C5) were prioritized for further evaluation. Docking and 1000 ns MD simulations showed that all five hits occupied the MTDH-recognition groove on SND1 and perturbed the MTDH-SND1 interface to different extents. MM/PBSA analysis indicated that all compounds weakened the protein-protein interaction, while protein-ligand binding free-energy calculations identified C1 and C2 as the strongest binders. Free-energy landscape analysis further showed that ligand binding reshaped the conformational space of the complex, with C2 favoring a particularly confined low-energy state. Experimental validation using split-luciferase complementation assays confirmed concentration-dependent disruption of the MTDH-SND1 interaction by all five compounds. In the cell-free assay, C1 and C2 were the most potent disruptors, and they remained the most active compounds in the cell-based format while showing minimal interference in the linked-luciferase counterscreen. Overall, this study identifies C1 and C2 as promising lead disruptors of the MTDH-SND1 interaction and expands the chemical space for targeting this oncogenic protein-protein interface.</p>

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Discovery of 1 H-Pyrrolo[2,3-b]pyridine-3-sulfonamides as disruptors of the oncogenic MTDH-SND1 Protein-Protein interaction through integrated in silico and in vitro screening

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Emadeldin M. Kamel,
  • Sally Mostafa Khadrawy,
  • Ahmed A. Allam,
  • Haifa E. Alfassam,
  • Adil Abalkhail,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

The metadherin (MTDH)-staphylococcal nuclease and tudor domain containing 1 (SND1) protein-protein interaction is a validated oncogenic driver implicated in cancer cell survival, metastasis, and immune evasion, making it an attractive therapeutic target. In the present study, we applied an integrated in silico-in vitro workflow to identify novel small-molecule disruptors of the MTDH-SND1 interaction from a focused library of 824 1 H-pyrrolo[2,3-b]pyridine-3-sulfonamides. Following diversity, purchasability, and drug-likeness filtering, the library was screened by molecular docking against the MTDH-binding region of SND1, and the top candidates were refined by short molecular dynamics (MD) simulations and MM/PBSA rescoring. Five compounds (C1-C5) were prioritized for further evaluation. Docking and 1000 ns MD simulations showed that all five hits occupied the MTDH-recognition groove on SND1 and perturbed the MTDH-SND1 interface to different extents. MM/PBSA analysis indicated that all compounds weakened the protein-protein interaction, while protein-ligand binding free-energy calculations identified C1 and C2 as the strongest binders. Free-energy landscape analysis further showed that ligand binding reshaped the conformational space of the complex, with C2 favoring a particularly confined low-energy state. Experimental validation using split-luciferase complementation assays confirmed concentration-dependent disruption of the MTDH-SND1 interaction by all five compounds. In the cell-free assay, C1 and C2 were the most potent disruptors, and they remained the most active compounds in the cell-based format while showing minimal interference in the linked-luciferase counterscreen. Overall, this study identifies C1 and C2 as promising lead disruptors of the MTDH-SND1 interaction and expands the chemical space for targeting this oncogenic protein-protein interface.