The effect of podophyllotoxin as an inducer of apoptosis using molecular docking method

Podophyllotoxin is used as one of the main treatments for genital warts. It is a precursor of etoposide and teniposide, which is used in the treatment of various cancers. Despite a large number of cancer studies, the exact mechanism of podophyllotoxin remains unknown. Chemotherapy drugs reduce cancer cells by inducing apoptosis. The regulation of the apoptotic pathway has been extensively studied in pharmaceutical research. The process of induction of apoptosis is performed by caspases. Suppression of enzymatic activity of adult caspases occurs in cancer cells in the presence of specific members of the IAPs family such as XIAP, cIAP1, and Survivin. By specifically binding Smac-mimetics to negative apoptosis regulators, inhibition of IAPs-mediated caspases is eliminated and apoptosis is induced. The development of Smac-mimetics as new anticancer drugs has been targeted. In the present study, bioinformatics was used to investigate the mechanism of action of podophyllotoxin as a Smac-mimetics on possible important routes of apoptosis.

Molecular docking method was used to calculate the molecular interaction of podophyllotoxin with proteins associated with initiator and effector caspases including XIAP / cAIP1-BIR3 and Survivin, as well as Bcl-2 and EGFR. The theoretical binding site of podophyllotoxin on these anti-apoptotic proteins was determined as an inhibitor to obtain information on the initial interaction, free binding energy and inhibition constant by molecular docking method.

The proapoptotic activity of podophyllotoxin as an apoptotic-inducing agent is associated with the signaling pathways of caspases 3, 7, 8, and 9. The key activation mechanisms of these caspases may be due to podophyllotoxin binding and induction of conformational changes at active sites of the XIAP / cAIP1-BIR3 and Survivin located near or at the same Smac-mimetics binding site. Three strong hydrogen bonds with the amino acids Tyr108, Ser117 and Glu118 play important roles in the stabilization of the Bcl-2-podophyllotoxin complex. Podophyllotoxin, similar to EGFR inhibitors, forms several hydrophobic interactions and two strong hydrogen bonds with Thr830 and Met769 with a bond-free energy of -7.85 kcal / mol and an inhibition constant of Ki = 1.76 µM.

Induction of apoptosis in cancer cells by podophyllotoxin can be attributed to several different mechanisms. Predicted binding conformations showed that podophyllotoxin had valuable inhibitory potential. Therefore, podophyllotoxin may be considered as an effective anticancer agent for further research into drug development.