Multi‐targeted Drug Repurposing Approach for Breast Cancer via Integrated Functional Network Analysis

Abstract

The present study focuses on the interconnected functional network of altered metabolism and EMT (epithelial to mesenchymal transition) signaling in breast cancer. We have interlinked the metabolic and EMT signaling circuits and selected Insulin receptor (IR), Integrin beta 1 (ITGB1), and CD36 as target proteins based on network analysis. Extensive computational approaches discerned the potential drug molecules from the library of 1293 FDA‐approved drugs to block all three target proteins. Using molecular docking, molecular dynamics simulation, and MMPBSA binding free energy studies, Capmatinib, Ponatinib, Naldemedine, and Pimozide were identified as potential repurposed drugs to block the function of all three target proteins. Among in silico selected candidate drugs, Pimozide, a known anti‐psychotic drug, was further validated using in‐vitro studies for its anti‐cell proliferative potential on breast cancer cell lines (namely, MCF7, MDAMB231 and MDAMB468). The inhibitory concentration (IC50) values of MCF7, MDAMB231 and MDAMB468 was found to be 16.26 μM, 20.82 μM and 13.10 μM, respectively. The effect of Pimozide on EMT‐induced MDAMB231 and MDAMB468 cells was evident from their IC50 values of 7.85 μM and 6.83 μM, respectively. The potent anti‐cancer property of Pimozide has opened up avenues for drug repurposing towards ‘multi‐targeted therapy’ in EMT dynamics.

Targeting human thymidylate synthase: Ensemble-based virtual screening for drug repositioning and the role of water

“…Given the oral bioavailability, inability to cross the blood brain barrier (BBB) and the safety pro le of Naldemedine, the drug presents a good choice for repositioning. Indeed, Naldemedine showed potential for drug repurposing against a number of diseases and targets, including breast cancer, COVID-19 [119,120]. Therefore, all the three drugs considered can be repurposed to target hTS.…”

Drug repurposing for viral cancers: A paradigm of machine learning, deep learning, and virtual screening‐based approaches

“…Structure-based screening methods have contributed equally to drug repurposing efforts starting from the start of in silico [200][201][202][203] approaches such as molecular docking. [204][205][206] Generally, structurebased VS ranks potential drug molecules against the protein target of interest which leads to reduction in experimental cost. 114,[207][208][209] Thus, normally used approaches use the structure of small molecule and protein and predict the binding affinity [210][211][212] as shown in method for observing the allowed interaction of atoms and molecules over certain period has also been used in drug repurposing for virus associated cancers Figure 6A.…”

“…Structure‐based screening methods have contributed equally to drug repurposing efforts starting from the start of in silico 200–203 approaches such as molecular docking 204–206 . Generally, structure‐based VS ranks potential drug molecules against the protein target of interest which leads to reduction in experimental cost 114,207–209 .…”

“…Similarly, there are multiple other drug repurposing frameworks which have been deployed for viral diseases such as viral cancers. Molecular dynamics, 205,213–217 a computer simulation method for observing the allowed interaction of atoms and molecules over certain period has also been used in drug repurposing for virus associated cancers Figure 6A. Molecular dynamics is used as a standalone approach or in combination with ML and DL approaches (Figure 5C).…”

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

“…Contactin-1 ( CNTN -1), a neuronal cell adhesion molecular, was not only involved in the nervous system development including axon guidance, synapse formation, and nerve impulse conduction, but also played a vital role in lymphangiogenesis, lymphatic metastasis, and proliferation of many epithelial malignancies including prostate cancer, hepatocellular cancer, breast cancer, and lung cancer ( Bamodu et al, 2020 ; Cao et al, 2021 ; Chen et al, 2021 ; Kandasamy et al, 2022 ). Additionally, in our prior studies, CNTN -1 upregulation was revealed to increase metastasis, invasion, and chemoresistance in lung adenocarcinoma cells with cisplatin resistance ( Zhang et al, 2015 ).…”