Armaghane Danesh Bimonthly Journal (Jul 2021)
The Effect of Podophyllotoxin as an Inducer of Apoptosis Using Molecular Docking Method
Abstract
Background and aim: 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. Suppression of enzymatic activity of adult caspases occurs in cancer cells in the presence of specific members of the inhibitor of apoptosis proteins (IAPs) family such as X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis proteins (cIAP1), and Survivin. By specifically binding a second mitochondria-derived activator of caspases-mimetics (Smac-mimetics) to negative apoptosis regulators, inhibition of IAPs-mediated caspases is eliminated and apoptosis is induced. The aim of the present study was used to determine the mechanism of action of podophyllotoxin as an inducer of apoptosis using molecular docking method. Methods: The present bioinformatics study was conducted in 2020. Molecular docking method was used to calculate the molecular interaction of podophyllotoxin with proteins associated with initiator and effector caspases including baculovirus IAP repeat (BIR3) of XIAP / cAIP1 and Survivin, as well as B-cell lymphoma-2 (Bcl-2) and epidermal growth factor receptor (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 collected data were analyzed using different software and compared with the results of related articles. Results: 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. Conclusion: 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.
