In Silico Screening of Flavonoids Against Cancer-Associated Molecular Targets: Molecular Docking and Molecular Dynamics Approaches

Background: Molecular docking and molecular dynamics provide complementary descriptions of ligand recognition, but their numerical outputs require careful interpretation. This study evaluates flavonoid screening against cyclin-dependent kinase 8 (CDK8), a cancer-associated transcriptional regulator. Methods: Screening counts, docking scores of ten prioritized flavonoids and five reference compounds, physicochemical predictions, principal-component variances, and endpoint energy estimates were analyzed, and ranking differences, selection fractions, and cumulative principal-component contributions were recalculated. Results: Of 800 flavonoids screened, 180 were selected as docking hits and 91 were retained after drug-likeness filtering (22.50% and 11.38% of the initial library, respectively). The ten prioritized docking scores ranged from −10.7 to −9.8 kcal/mol (median −10.05 kcal/mol). Lupalbigenin (ZINC000005854718) ranked first at −10.7 kcal/mol, only 0.2 kcal/mol more favorable than linifanib. All ten prioritized compounds had zero Lipinski violations; one had a PAINS alert and six had at least one Brenk alert. Across the five simulated temperatures, the first three principal components explained 50.27–66.01% of variance. Six endpoint energy procedures gave values from −45.08 to −18.42 kcal/mol. Conclusions: The data support lupalbigenin as a computational candidate for CDK8 inhibition, but the narrow docking margins and method-dependent energy estimates do not justify claims of superior potency or validated anticancer activity. Experimental validation and more rigorous simulation protocols are needed before stronger mechanistic conclusions can be drawn.