فهرست نشریات علمی دسترسی آزاد ایران

Osthol, a coumarin derivative, exhibits potential anticancer activity, yet its mechanisms against colon cancer remain unclear and constitute an unexplored area for further investigation to advance its development as a strong anticancer agent. The geometry of osthol was optimized using DFT/B3LYP/6-311G, confirmed by frequency analysis, and key quantum descriptors (FMOs, reactivity indices, dipole, polarizability, and hyperpolarizability) were computed. To assess osthol’s physicochemical, drug-likeness, and anti-colon cancer mechanisms using computational and experimental approaches. Osthol’s physicochemical and ADME properties were analyzed via SwissADME, drug-likeness using Molsoft, and toxicity with Protox-3.0. Osthol and colon cancer targets were sourced from Comparative Toxicogenomics Database, ChEMBL, SwissTargetPrediction, and GeneCards (GIFTS score ≥55%). Intersecting targets were identified with Venny 2.0, and protein–protein interactions (PPI) were observed using Cytoscape and STRING with CytoHubba for hub gene identification. Gene Ontology (GO) and pathway enrichment were carried out through the STRING database, and the resulting datasets were portrayed as chord plots using SRPlot. Molecular docking of osthol with AKT1, BCL2, and CASP3 was conducted using CB-DOCK2. In vitro, HT-29 colon cancer and CCD-841-CoN normal cells were treated with osthol (0–64 μM). Cytotoxicity, colony formation, apoptosis (Annexin V-FITC/PI), and protein expression (AKT1, BCL2, CASP3) were assessed via MTT, colony formation, flow cytometry, and western blotting assays. DFT analysis of Osthol revealed a stable optimized geometry, a 4.35 eV HOMO–LUMO gap with charge-transfer character, and favorable global reactivity descriptors. Osthol showed favorable drug-likeness (MW: 244.31, AlogP: 3.74, TPSA: 39.44, oral bioavailability: 38.75%) and no predicted toxicity. Intersection analysis revealed 145 shared targets, forming a PPI network (145 nodes, 562 edges, p<1.0×10⁻¹⁶) with hub genes AKT1, BCL2, and CASP3. GO/KEGG analyses highlighted apoptosis, stress responses, and colorectal cancer pathways. Docking showed strong binding: BCL2 (-10.3 kcal/mol), AKT1 (-8.3 kcal/mol), CASP3 (-6.0 kcal/mol). Osthol reduced HT-29 cell viability and cell colonies, without a significant effect on normal cells, and induced apoptosis (Annexin V/PI) by downregulating AKT1/BCL2 and upregulating cleaved CASP3 expression. Osthol’s drug-like properties and multi-target anti-colon cancer activity support its therapeutic potential.