In Silico Investigation of Candidate Anticancer Targets for Aryltetralin Lignans Previously Reported from Cleistanthus Species

Aryltetralin lignans isolated from the fruits of Cleistanthus species exhibit substantial cytotoxic activity, although the molecular interactions underlying these effects remain incompletely understood. This study combined computational target investigation with previously published experimental chemical characterization and cytotoxic evidence and no new isolation or cytotoxicity experiments were carried out. Cleistantoxin, 7-hydroxypicropolygamain, neo-cleistantoxin, cleisindoside A, cleisindoside D, and cleistonkinin D were previously isolated from C. indochinensis, C. tonkinensis, C. eberhardtii and characterized by complementary spectroscopic methods. Cleistantoxin showed potent activity against MCF-7, multidrug-resistant MCF-7R, and HT29 cells, with reported IC50 values of 0.036, 0.014, and 0.035 μM, respectively. Structural similarity to podophyllotoxin-derived anticancer agents guided the investigation of DNA topoisomerase IIβ, Bcl-2, and p53 Y220C as candidate targets. Docking with AutoDock Vina-GPU 2.1 was validated by redocking the co-crystallized inhibitors (RMSD < 2 Å at the TOP2B and Bcl-2 sites; the p53 Y220C control is reported for both receptor preparations), and selected complexes were simulated in triplicate for 100 ns, followed by MM-GBSA calculations and ADMET predictions. Cleisindoside A and D kept etoposide-like hydrogen bonds to DNA in the TOP2B–DNA complex. Their MM-GBSA binding energies were −78.40 ± 3.73 and −81.90 ± 7.84 kcal·mol−1 for two ligand copies, comparable to −79.62 ± 5.14 kcal·mol−1 for etoposide. In Bcl-2, S-10r was clearly more favorable than cleisindoside D. The predicted pharmacokinetic profiles differentiated the aglycones from the glycosides and identified potential cytochrome P450 inhibition liabilities. By linking previously reported experimentally characterized natural products and cytotoxic evidence with molecular modeling, this study provides testable hypotheses for the molecular recognition of Cleistanthus lignans. Direct biochemical and mechanism-focused cellular studies are nevertheless required to validate the proposed targets.