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<p>The metadherin (MTDH)–staphylococcal nuclease domain-containing protein 1 (SND1) interaction is an oncogenic protein–protein interaction (PPI) linked to cancer cell survival, progression, and metastasis, but small-molecule disruptors remain scarce. Here, we developed an integrated in silico-to-in vitro workflow to discover 1&#xa0;H-indazole-3-carboxylic acid derivatives as MTDH–SND1 PPI disruptors. A focused library of 399 compounds was processed through a funnel-based screening pipeline comprising drug-likeness and PAINS/reactivity filtering, diversity/purchasability triage, AutoDock Vina docking, and short molecular dynamics (MD) refinement with MM/PBSA rescoring. Three compounds (IC1–IC3) were prioritized for 1,000-ns MD simulations and mechanistic analysis. Docking and MD showed that all three compounds bind the targeted SND1 interfacial groove, but with different functional consequences. PPI-oriented MM/PBSA, FEL, and trajectory-based disruption metrics consistently ranked IC2 as the strongest predicted disruptor, IC1 as a moderate disruptor, and IC3 as a non-disruptive interfacial binder despite favorable direct binding energy. Free-energy landscape analysis further showed that IC2 most strongly remodeled the conformational landscape of the MTDH–SND1 complex, whereas IC3 remained confined to a more stable, non-disruptive basin. Split-luciferase complementation assays validated these predictions. In cell-free assays, IC<sub>50</sub> values were 2.94 ± 0.35 µM (IC2), 4.19 ± 0.48 µM (IC1), and 116.29 ± 5.21 µM (IC3). In SCP28 cell-based assays, IC<sub>50</sub> values were 12.08 ± 1.4 µM, 18.0 ± 2.1 µM, and 337 ± 12.9 µM, respectively, while linked-luciferase counter-screen IC<sub>50</sub> values exceeded 1,000 µM for all compounds. ADMETlab 3.0 profiling identified IC1 as the most balanced developability candidate, whereas IC2 remained the lead efficacy-prioritized hit for subsequent optimization efforts.</p>

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1H-Indazole-3-Carboxylic Acid Derivatives as Disruptors of the Oncogenic MTDH–SND1 Protein–Protein Interaction: An In Silico-to-In Vitro Study

  • 期刊论文

  • 发表日期：

    2026年5月28日

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  • Emadeldin M. Kamel,
  • Sally Mostafa Khadrawy,
  • Ahmed A. Allam,
  • Sarah I. Othman,
  • Adil Abalkhail,
  • Faris F. Aba Alkhayl,
  • Al Mokhtar Lamsabhi

摘要

The metadherin (MTDH)–staphylococcal nuclease domain-containing protein 1 (SND1) interaction is an oncogenic protein–protein interaction (PPI) linked to cancer cell survival, progression, and metastasis, but small-molecule disruptors remain scarce. Here, we developed an integrated in silico-to-in vitro workflow to discover 1 H-indazole-3-carboxylic acid derivatives as MTDH–SND1 PPI disruptors. A focused library of 399 compounds was processed through a funnel-based screening pipeline comprising drug-likeness and PAINS/reactivity filtering, diversity/purchasability triage, AutoDock Vina docking, and short molecular dynamics (MD) refinement with MM/PBSA rescoring. Three compounds (IC1–IC3) were prioritized for 1,000-ns MD simulations and mechanistic analysis. Docking and MD showed that all three compounds bind the targeted SND1 interfacial groove, but with different functional consequences. PPI-oriented MM/PBSA, FEL, and trajectory-based disruption metrics consistently ranked IC2 as the strongest predicted disruptor, IC1 as a moderate disruptor, and IC3 as a non-disruptive interfacial binder despite favorable direct binding energy. Free-energy landscape analysis further showed that IC2 most strongly remodeled the conformational landscape of the MTDH–SND1 complex, whereas IC3 remained confined to a more stable, non-disruptive basin. Split-luciferase complementation assays validated these predictions. In cell-free assays, IC50 values were 2.94 ± 0.35 µM (IC2), 4.19 ± 0.48 µM (IC1), and 116.29 ± 5.21 µM (IC3). In SCP28 cell-based assays, IC50 values were 12.08 ± 1.4 µM, 18.0 ± 2.1 µM, and 337 ± 12.9 µM, respectively, while linked-luciferase counter-screen IC50 values exceeded 1,000 µM for all compounds. ADMETlab 3.0 profiling identified IC1 as the most balanced developability candidate, whereas IC2 remained the lead efficacy-prioritized hit for subsequent optimization efforts.