Cancer remains one of the leading causes of global mortality, necessitating novel therapeutic strategies. Liver X Receptors (LXRα and LXRβ) and the Farnesoid X Receptor (FXR) are nuclear receptors tha Show more
Cancer remains one of the leading causes of global mortality, necessitating novel therapeutic strategies. Liver X Receptors (LXRα and LXRβ) and the Farnesoid X Receptor (FXR) are nuclear receptors that regulate lipid and cholesterol homeostasis, bile acid metabolism, inflammation, and immune response pathways intricately linked to cellular dysregulation in oncogenesis. Despite their therapeutic potential, these receptors remain underexplored targets in cancer research. This study implements an extensive suite of computational strategies to identify and evaluate potential modulators of LXRα/β and FXR, through virtual screening using resveratrol as the lead scaffold, followed by drug-likeness evaluation and toxicity profiling. Molecular docking (MVD, AutoDock and ML-PLIC) identified C144 (AZD7762), a well-established CHK1 kinase inhibitor, as the top-ranked ligand, demonstrating superior binding affinity and conformational stability via convergent interaction mechanisms. Additionally, reactivity descriptors derived from density functional theory (DFT) and frontier molecular orbital (FMO) analyses further substantiated its favorable electronic properties and chemical stability. Structural pharmacophore mapping using LigandScout confirmed pharmacophoric alignment with receptor active sites, while bioactivity profiles predicted high efficacy. Extensive quantum mechanical analyses (MEP, NBO, Mulliken/NPA, NCI, RDG, ELF, LOL, BSA, HAS) revealed favorable electronic characteristics, stability, charge distribution, and interaction potential. CLC-Pred, biotransformation (RA), pharmacokinetic profiling, molecular dynamics simulations, MM/PBSA and Shermo-based thermodynamic predictions further validated its biostability and systemic compatibility. These findings position C144 (AZD7762) as a promising anticancer candidate targeting LXRα, LXRβ, and FXR pathways. Further optimization and validation through in vitro and in vivo studies are essential for advancing these findings toward clinical application. Show less