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<p>The ATPase activity of Hsp90 is critical for cancer progression, as it maintains the stability of oncogenic proteins, thereby supporting tumor cell survival. Although small-molecule inhibitors targeting this activity have shown preclinical promise, toxicity and insufficient efficacy have hindered their progress in clinical trials. Accordingly, expanding the search for novel Hsp90 inhibitors remains paramount. Spirodioxynaphthalenes, a rapidly expanding class of fungal secondary metabolites, exhibit a remarkable breadth of bioactive properties, including antitumor, antibacterial, antifungal, and enzymatic inhibitory activities. This study employed an <i>in-silico</i> methodology to identify spirodioxynaphthalene derivatives as potential inhibitors of Hsp90’s ATPase activity. We identified thirteen spirodioxynaphthalenes from natural product databases as potential inhibitors of Hsp90 ATPase activity. These compounds, with their favorable drug-like properties, promising predicted pharmacokinetics and cytotoxicity, and potent binding energies ranging from − 10.016 to -10.636&#xa0;kcal/mol, emerge as compelling candidates for further optimization. Their binding interactions, which reveal key hydrogen bonds and hydrophobic interactions with catalytic residues Lys58, Gly97, and Thr184, bolster their potential as Hsp90 inhibitors. Moreover, molecular dynamics simulations of the top-ranked molecules from the docking studies showed improved binding stability, consistent intermolecular interactions, and favorable conformational behavior within the Hsp90 binding pocket throughout the simulation. Collectively, these findings strongly suggest that spirodioxynaphthalenes could serve as a new chemotype for developing Hsp90-targeted cancer therapeutics, offering hope for the future of cancer treatment. Additional mechanistic validation and preclinical development are needed to move these compounds toward clinical application.</p>

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In silico identification of spirodioxynaphthalenes as promising Hsp90 inhibitors

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Adam A. Aboalroub,
  • Mansour Al-Sayed Ahmad,
  • Belal O. Al-Najjar

摘要

The ATPase activity of Hsp90 is critical for cancer progression, as it maintains the stability of oncogenic proteins, thereby supporting tumor cell survival. Although small-molecule inhibitors targeting this activity have shown preclinical promise, toxicity and insufficient efficacy have hindered their progress in clinical trials. Accordingly, expanding the search for novel Hsp90 inhibitors remains paramount. Spirodioxynaphthalenes, a rapidly expanding class of fungal secondary metabolites, exhibit a remarkable breadth of bioactive properties, including antitumor, antibacterial, antifungal, and enzymatic inhibitory activities. This study employed an in-silico methodology to identify spirodioxynaphthalene derivatives as potential inhibitors of Hsp90’s ATPase activity. We identified thirteen spirodioxynaphthalenes from natural product databases as potential inhibitors of Hsp90 ATPase activity. These compounds, with their favorable drug-like properties, promising predicted pharmacokinetics and cytotoxicity, and potent binding energies ranging from − 10.016 to -10.636 kcal/mol, emerge as compelling candidates for further optimization. Their binding interactions, which reveal key hydrogen bonds and hydrophobic interactions with catalytic residues Lys58, Gly97, and Thr184, bolster their potential as Hsp90 inhibitors. Moreover, molecular dynamics simulations of the top-ranked molecules from the docking studies showed improved binding stability, consistent intermolecular interactions, and favorable conformational behavior within the Hsp90 binding pocket throughout the simulation. Collectively, these findings strongly suggest that spirodioxynaphthalenes could serve as a new chemotype for developing Hsp90-targeted cancer therapeutics, offering hope for the future of cancer treatment. Additional mechanistic validation and preclinical development are needed to move these compounds toward clinical application.