Exploring Moringa oleifera Phytochemicals as Potential Inhibitors for HIF- 1α/VEGF/GLUT1 pathway in Breast Cancer Using Molecular Docking, MD Simulations, and DFT Analysis

Breast cancer is among the most heterogeneous and aggressive diseases and a foremost cause of death in women globally. Hypoxic activation of HIF-1α in breast cancers triggers the transcription of a battery of genes encoding proteins that facilitate tumor growth and metastasis and is correlated with a poor prognosis. Based on the reported cytotoxic and anti-cancer properties of Moringa oleifera (Mo) , this study explores the inhibitory effect of bioactive compounds AA and BITC from Moringa oleifera and Breast cancer target proteins HIF-1α, VEGF, and GLUT1 in silico . The X-ray crystallographic structures of HIF-1α, VEGF, and GLUT1 were sourced from the Protein Data Bank (PDB) and docked with 3D PubChem structures of bioactive compounds of AA and BITC using AutoDock Vina, and binding modes were analyzed using Discovery Studio. further drug-likeness, oral bioavailability, ADME, and toxicity profiles were analyzed using SwissADME, ADMETSaR, and ADMETlab 3.0 web server. Complexes were subjected to molecular dynamic simulation (MDS) analysis using Desmond Schrodinger v2019. Then, density functional theory (DFT) studies were performed to measure the active compound’s reactivity, with the help of Gaussian 09 software. Molecular docking results indicated that the ligands interact strongly with the target HIF-1α, VEGF, and GLUT1 receptors through Hydrogen bonds and hydrophobic interactions. These compounds showed favorable drug-like and pharmacokinetic properties, possessed no substantial toxicity, and were fairly bioavailable. The root-mean-square deviation (RMSD) graphs obtained through the molecular dynamic simulations indicated the true bonding interactions, further validated using the root-mean-square fluctuation (RMSF) graphs which provided a better understanding of the amino acids present in the proteins responsible for the molecular motions and fluctuations. Results suggested that the compounds possess strong potential in developing putative lead compounds targeting HIF-1α that are safe natural plant-based drugs against Breast cancer.