Molecular modeling studies of the effects of withaferin A and its derivatives against oncoproteins associated with breast cancer stem cell activity

Abstract

Cancer stem cells (CSCs) in breast cancers are considered to be a major cause of tumor recurrence and metastasis, which lead to chemotherapeutic failures and poor survival rates among breast cancer patients. Hence, this study attempted to evaluate the anti-tumor potential of a bioactive withanolide compound, withaferin A (WFA), against the molecular targets that maintain the stemness of breast cancer stem cells, using in silico molecular modeling approach. The crystal structures of potential breast cancer stem cell targets—HSP70, HSP90, NFκB, and BRCA1 were retrieved from PDB. The 2D structures of WFA, its analogs, along with doxorubicin and vinblastine were retrieved from the PubChem database. WFA and withaferin A diacetate exhibited strong receptor-ligand interactions for the target macromolecules. Their binding energy values ranged between –55.241 and –40.250 kcal/mol. Compared to doxorubicin, WFA markedly inhibited the growth and decreased the viability of MCF-7-derived breast cancer stem cells, with an IC50 value of 1.476 μM for 48 h. Therefore, our results indicate that WFA and its derivatives could be promising anti-tumor agents against breast cancer stem cells. Further in vitro studies are warranted in order to gain a greater understanding of the action of this compound in a physiological setting.