Evaluating chemotherapeutic potential of soya-isoflavonoids against high penetrance genes in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer (BC) associated with a poor prognosis. Owing to the structural similarity with 17-β-estradiol, consumption of soya-isoflavonoids are associated with a reduced rate of hormone-receptive BC incidence, but their role in TNBC is not deciphered in detail. This present study thus aims to investigate the therapeutic binding dynamics of dietary soya-flavonoids with the six high penetrance (HP) receptors in TNBC, viz. BRCA1, BRCA2, PALB2, PTEN, STK11 and TP53. Out of the 14 soya-flavonoids screened based on ADMET descriptors and several other physicochemical, bioavailability, drug and lead-likeness properties, four hits were shortlisted (Daidzein, Genistein, Glycitein and Biochanin A). Docking and molecular dynamics (MD) simulation revealed Genistein as the most potential multi-target inhibitor of the six TNBC HP genes. Additionally, Genistein exhibited excellent binding specificity with PTEN, a potent mediator of the PI3K signaling pathway in TNBC. The binding interaction of PTEN and Genistein was further compared against a standardized FDA-approved chemotherapeutic inhibitor, Olaparib, computed through various MD trajectory analysis, principal component analysis and computation of free energy landscape. This study reveals a comparatively better binding dynamics of PTEN-Genistein than PTEN-Olaparib. With a significant global surge in biomarker-based precision therapeutics in oncology, the results of this exhaustive in-silico study thus encourage the prospect of validating PTEN as a druggable target of Genistein, a unique drug-receptor combination in the future.Communicated by Ramaswamy H. Sarma.