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Abstract

Breast cancer has been a major reason of mortality among women affected by cancer, with current strategies often constrained by challenges such as suboptimal drug bioavailability, systemic toxicity, and resistance. This study employed a computational strategy to design and explores the therapeutic potential of eucalyptol, along with its 342 structural analogues, as prospective agents against nine critical breast cancer receptors (BRCA1, BRCA2, COX-2, EGFR, ER-α, mTOR, PPAR-γ, PR, and SIRT2). Utilizing molecular docking methodologies, we evaluated the binding affinities of these compounds against these receptors, which are instrumental in tumor progression, therapeutic resistance, and metabolic dysregulation. Virtual screening identified OZ-082 as a lead multi-targeting candidate, exhibiting strong and consistent binding across multiple key targets such as -9.1 kcal/mol with SIRT2, -8.8 kcal/mol with COX-2, BRCA-1 as -5.5 kcal/mol, BRCA-2 had -6.5 kcal/mol, EGFR -7 kcal/mol, ER-α exhibits -9 kcal/mol, mTOR -8.5 kcal/mol, PPAR-γ have -7 kcal/mol, and PR have -7 kcal/mol respectively and a high enrichment factor (EF₁₋₄% = 12.5) across key targets. Comprehensive ADMET analyses performed using SwissADME and pkCSM tools revealed that OZ-082 possesses favorable drug-likeness, high gastrointestinal absorption (95%), no hepatotoxicity, and minimal CYP450 inhibition risk, marking a significant improvement over the parent eucalyptol. These findings highlight the potential of eucalyptol derivative OZ-082 as a promising lead compound to address the limitations of current therapies by modulating diverse molecular pathways involved in breast cancer pathogenesis. Moreover, this research highlights the value of computational drug discovery in expediting the identification of promising therapeutic candidates. Future validation will require In vitro cytotoxicity assays e.g., in MCF-7 and MDA-MB-231 cells) and In vivo efficacy studies in xenograft models to validate the anticancer efficacy, safety profile, and underlying mechanisms of OZ-082, thereby advancing the development of targeted, less toxic, and more effective therapeutic options for breast cancer

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