An integrated computational approach to screening of alkaloids inhibitors of TBX3 in breast cancer cell lines

TBX3 is an ancient and evolutionarily conserved family member of T-box transcription factors that acts as a key regulator in embryonic development and organogenesis. It is often overexpressed in various epithelial and mesenchymal malignancies which has a significant impact on various hallmarks of cancer, which mainly includes senescence shunt, apoptosis, anoikis, angiogenesis, and promoting metastatic and expansion of cancer stem cells. In addition to the role of TBX3 in early breast development, a number of studies have also confirmed the amplification of TBX3 in the occurrence and development of breast cancer. To overcome a major challenge in breast cancer treatment, resistance to current anti-cancer drug, it is important to develop new drug pipeline. In this study of different alkaloid molecules, to identify potential alkaloid inhibitors of TBX3, a structure based virtual screening was done involving molecular docking, ADME, toxicity analysis, molecular dynamics simulation. From our study 5 ligands named Jervine, Diflomotecan, Camptothecin, Vincamine, and Anoniane were primarily confirmed as potential inhibitors. The followed screening manner funnels out five potential compounds that have a high scoring function that emphasizes their high binding ability along with no toxicity effects. The molecular mechanics-generalized born surface area (MM-GBSA) and molecular dynamics (MD) simulation showed that Jervine along with Diflomotecan formed the stable complexes with TBX3 which makes it obvious that these two alkaloids can be introduced into the drug development pipeline and used as a new leader to develop new effective drugs against breast cancer. Communicated by Ramaswamy H. Sarma