Molecular binding signatures of Trigonella foenum-graecum compounds on cyclin-dependent kinase 4 for possible anti-cancer mechanism in breast cancer

Breast cancer (BC) continues to impose high epidemiological and socio-economic burden on female Homo sapiens, even in the face of new therapeutics. Of particular interest here is its neglected rise in low- and middle-income countries, thus necessitating the need for cost effective alternatives. The current understanding of a typical oncogenic BC cell dictates aberrant interplay, downstream the cyclin-dependent kinases (CDKs). CDKs play critical roles in the anomalous multiplicity of cancer cells and thus, represent interesting targets. In this report, structure-based virtual screening was carried out. The binding of compounds from Trigonella foenum-graecum (TF) to cyclin-dependent kinase 4 (CDK4) compared with that of standard drugs – Abemaciclib, Palbociclib and Ribociclib – was studied. In the light of palbociclib, a heuristic pipeline was designed to ensure specificity and selectivity of new inhibitors capable of antagonizing CDK4-mediated phosphorylation of retinoblastoma protein (Rb), a crucial step in abrogating neoplastic BC growth.  The 2D conformations of phytocompounds were downloaded and optimised before being docked into the active site of CDK4 protein. In silico protocol to predict the drug-likeness of lead compounds, was also carried out. Five (5) phytocompounds emerged with binding energies lower than the standard drugs. Upon screening of lead compounds for their drug-likeness, four emerged as drug candidates: Irilone, Calycosin, Daidzein and Formononetin, which complied with Lipinski’s “Rule of Five” (RO5). Compounds from TF were found to exhibit lower binding energies, compared to standard drugs and could be potent in cancer treatment, especially human epidermal growth factor receptor 2 (HER2)-positive (+) BC.